Studies Supporting Nunzia

The Anxiety areas in the brain significantly interferes with social development and learning:

The hippocampus is the part of the brain that is involved in memory forming, organizing, and storing. It is a limbic system structure that is particularly important in forming new memories and connecting emotions and senses, such as smell and sound, to memories. The hippocampus is a horseshoe shaped paired structure, with one hippocampus located in the left brain hemisphere and the other in the right hemisphere.

The hippocampus acts as a memory indexer by sending memories out to the appropriate part of the cerebral hemisphere for long-term storage and retrieving them when necessary.

The hippocampus is involved in several functions of the body including:

• Consolidation of new memory
• Emotional Responses
• Navigation
• Spatial Orientation
• Controlling anxiety can greatly improve therapies:
• Current anti-anxiety drugs are broad acting and usually ineffective
  • Valium, Prozac, amphetamines, anti-psychotics etc
  • These drugs are considered “Hit or Miss”, singly or in combination
• Positive targeted drugs are needed:
  • NUNZIA – a “Targeted Blocker”

NUNZIA is able to reduce the extra synapses which cause anxiety. When there is a rapid firing of synapse and the protein filters of the brain are functional, then anxiety occurs, but no or little affixations, but when the protein filters are not functional or functioning at full capacity, such as the FXMP protein, then anxiety can also produce affixations and other disorders, which are related to affixations or compulsory. We had thought that Fragile X or Autist people did not have the FXMP protein and was the root cause, but after much research, we did conclude that the FXMP protein filter was present, but not functioning at full capacity and functioned at different levels according the individual and therefore the consensus and conclusion was that the different levels of functionality of the FXMP could be the main cause of affixations and compulsory disorders at different levels in the individual.

Anxiety Systems and Disorders alone cause various problems, but when coupled with a malfunctioning FXMP protein the problems are exponential.

Symptoms of Anxiety:

According to the Mayo Clinic Staff: (www.mayoclinic.com Symptoms of Anxiety)

Common anxiety signs and symptoms include:

• Feeling nervous
• Feeling powerless
• Having a sense of impending danger, panic or doom
• Having an increased heart rate
• Breathing rapidly (hyperventilation)
• Sweating
• Trembling
• Feeling weak or tired
• Trouble concentrating or thinking about anything other than the present worry

Several types of anxiety disorders exist:

Separation anxiety disorder is a childhood disorder characterized by anxiety that is excessive for the developmental level and related to separation from parents or others who have parental roles.

Selective mutism is a consistent failure to speak in certain situations, such as school, even when you can speak in other situations, such as at home with close family members. This can interfere with school, work and social functioning.

Specific phobias are characterized by major anxiety when you’re exposed to a specific object or situation and a desire to avoid it. Phobias provoke panic attacks in some people.

Social anxiety disorder (social phobia) involves high levels of anxiety, fear and avoidance of social situations due to feelings of embarrassment, self-consciousness and concern about being judged or viewed negatively by others.

Panic disorder involves repeated episodes of sudden feelings of intense anxiety and fear or terror that reach a peak within minutes (panic attacks). You may have feelings of impending doom, shortness of breath, heart palpitations or chest pain.

Agoraphobia is anxiety about, and often avoidance of, places or situations where you might feel trapped or helpless if you start to feel panicky or experience embarrassing symptoms, such as losing control.

Generalized anxiety disorder:

Includes persistent and excessive anxiety and worry about activities or events — even ordinary, routine issues. The worry is usually out of proportion to the actual circumstance, is difficult to control and interferes with your ability to focus on current tasks. It often occurs along with other anxiety disorders or depression.

Substance-induced anxiety disorder is characterized by prominent symptoms of anxiety or panic that are a direct result of abusing drugs, taking medications, being exposed to a toxic substance or withdrawal from drugs.

Anxiety disorder due to a medical condition includes prominent symptoms of anxiety or panic that are directly caused by a physical health problem.

Specified anxiety disorder and unspecified anxiety disorder are terms for anxiety or phobias that don’t meet the exact criteria for any other anxiety disorders but are significant enough to be distressing and disruptive.

Other Disorders that NUNZIA can help:

Mayo Clinic Staff, (www.Maycoclinic.com.. OCD)

Factors that may increase the risk of developing or triggering obsessive-compulsive disorder include:

Family history: Having parents or other family members with the disorder can increase your risk of developing OCD stressful life events. If you’ve experienced traumatic or stressful events or you tend to react strongly to stress, your risk may increase. This reaction may, for some reason, trigger the intrusive thoughts, rituals and emotional distress characteristic of OCD.

Stressful events cause ANXIETY:

Cause: 

Mayo Clinic Staff (www.Maycoclinic.com.. OCD)

The cause of obsessive-compulsive disorder isn’t fully understood. Main theories include:

Biology: OCD may be a result of changes in your body’s own natural chemistry or brain functions. OCD may also have a genetic component, but specific genes have yet to be identified.

California Biotech has identified the chemistry function for Anxiety, which can trigger OCD.

Environment: Some environmental factors such as infections are suggested as a trigger for OCD, but more research is needed to be sure.

Complications:

By Mayo Clinic Staff, continued

Individuals with obsessive-compulsive disorder may have additional problems. Some of the problems below may be associated with OCD — others may exist in addition to OCD but not be caused by it.

• Inability to attend work, school or social activities
• Troubled relationships
• Overall poor quality of life
• Anxiety disorders**
• Depression
• Eating disorders***
• Suicidal thoughts and behavior
• Alcohol or other substance abuse***
• Contact dermatitis from frequent hand-washing: if frequent hand–washing is an affixation

• BOLD and Underlined and can be treated by NUNZIA.

All Anxiety Disorders as stated above, have been found to be the basis of Autistic Spectrum of Disorders (ASD).  As it is well known ASD includes many disorders that we are familiar with, such as: Autism, Fragile X, ADD, ADHD, PTSD OCD; and including some disorders that are also anxiety and glutamate based, but we may not have known, that this disorders are part of the same spectrum, such as: MS, Parkinson, and Dementia. It has been proven in several studies through out the world over the last twenty plus years, as stated and verified in this summary of more than three hundred studies.

General clinical implications

• Autoimmunity and antibody interactions with glutamate receptors and their subunit genes
• Excitotoxicity
• Neurodegeneration

Conditions with demonstrated associations to glutamate receptors

• Aching*
• Attention deficit hyperactivity disorder (ADHD)*
• Autism*
• Diabetes*
• Huntington’s disease
• Ischemia
• Multiple sclerosis*
• Parkinson’s disease (Parkinsonism)*
• Rasmussen’s encephalitis
• Schizophrenia
• Seizures*
• Other diseases suspected of glutamate receptor link
• Neurodegenerative diseases with a suspected excitotoxicity link

General clinical implications

Specific medical conditions and symptoms are discussed below.

Autoimmunity and antibody interactions with glutamate receptors and their subunit genes

Various neurological disorders are accompanied by antibody or autoantigen activity associated with glutamate receptors or their subunit genes (e.g. GluR3 in Rasmussen’s encephalitis,[31] and GluR2 in nonfamilial olivopontocerebellar degeneration.[32] In 1994 GluR3 was shown to act as an autoantigen in Rasmussen’s encephalitis, leading to speculation that autoimmune activity might underlie the condition.[33] Such findings “suggest” links between glutamate receptors and autoimmune interactions are possible and may be significant in some degenerative diseases,[32] however the exact role of such antibodies in disease manifestation is still not entirely known.[34]

Excitotoxicity

Overstimulation of glutamate receptors causes neurodegeneration and neuronal damage through a process called excitotoxicity. Excessive glutamate, or excitotoxins acting on the same glutamate receptors, overactivate glutamate receptors (specifically NMDARs), causing high levels of calcium ions (Ca2+) to influx into the postsynaptic cell.[35]

High Ca2+ concentrations activate a cascade of cell degradation processes involving proteases, lipases, nitric oxide synthase, and a number of enzymes that damage cell structures often to the point of cell death.[36] Ingestion of or exposure to excitotoxins that act on glutamate receptors can induce excitotoxicity and cause toxic effects on the central nervous system.[37] This becomes a problem for cells, as it feeds into a cycle of positive feedback cell death.

Glutamate excitotoxicity triggered by overstimulation of glutamate receptors also contributes to intracellular oxidative stress. Proximal glial cells use a cystine/glutamate antiporter (xCT) to transport cystine into the cell and glutamate out. Excessive extracellular glutamate concentrations reverse xCT, so glial cells no longer have enough cystine to synthesize glutathione (GSH), an antioxidant.[38] Lack of GSH leads to more reactive oxygen species (ROSs) that damage and kill the glial cell, which then cannot reuptake and process extracellular glutamate.[39] This is another positive feedback in glutamate excitotoxicity. In addition, increased Ca2+ concentrations activate nitric oxide synthase (NOS) and the over-synthesis of nitric oxide (NO). High NO concentration damages mitochondria, leading to more energy depletion, and adds oxidative stress to the neuron as NO is a ROS.[40]

Neurodegeneration

In the case of traumatic brain injury or cerebral ischemia (e.g., cerebral infarction or hemorrhage), acute neurodegeneration caused by excitotoxicity may spread to proximal neurons through two processes. Hypoxia and hypoglycemia trigger bioenergetic failure; mitochondria stop producing ATP energy. Na+/K+-ATPase can no longer maintain sodium/potassium ion concentration gradients across the plasma membrane. Glutamate transporters (EAATs), which use the Na+/K+ gradient, reverse glutamate transport (efflux) in affected neurons and astrocytes, and depolarization increases downstream synaptic release of glutamate.[41] In addition, cell death via lysis or apoptosis releases cytoplasmic glutamate outside of the ruptured cell.[42] These two forms of glutamate release cause a continual domino effect of excitotoxic cell death and further increased extracellular glutamate concentrations.

Glutamate receptors’ significance in excitotoxicity also links it to many neurogenerative diseases. Conditions such as exposure to excitotoxins, old age, congenital predisposition, and brain trauma can trigger glutamate receptor activation and ensuing excitotoxic neurodegeneration. This damage to the central nervous system propagates symptoms associated with a number of diseases.[43]

Conditions with demonstrated associations to glutamate receptors

A number of diseases in humans have a proven association with genetic mutations of glutamate receptor genes, or autoantigen/antibody interactions with glutamate receptors or their genes. Glutamate receptors and impaired regulation (in particular, those resulting in excessive glutamate levels) are also one cause of excitotoxicity (described above), which itself has been implicated or associated with a number of specific neurodegenerative conditions where neural cell death or degradation within the brain occurs over time.[39][43]

Excessive synaptic receptor stimulation by glutamate is directly related to a many conditions. Magnesium is one of many antagonists at the glutamate receptor, and magnesium deficiencies have demonstrated relationships with many glutamate receptor-related conditions.[44]

Glutamate receptors have been found to have an influence in ischemia/stroke, seizures, Parkinson’s disease, Huntington’s disease, and aching,[45] addiction[46] and an association with both ADHD[47] and autism.[48]

In most cases these are areas of ongoing research.

Aching

Hyperalgesia is directly involved with spinal NMDA receptors. Administered NMDA antagonists in a clinical setting produce significant side effects, although more research is being done in intrathecal administration.[37] Since spinal NMDA receptors link the area of pain to the brain’s pain processing center, the thalamus, these glutamate receptors are a prime target for treatment. One proposed way to cope with the pain is subconsciously through the visualization technique.[49]

Attention deficit hyperactivity disorder (ADHD)

In 2006 the glutamate receptor subunit gene GRIN2B (responsible for key functions in memory and learning) was associated with ADHD.[50] This followed earlier studies showing a link between glutamate modulation and hyperactivity (2001),[51][51] and then between the SLC1A3 solute carrier gene-encoding part of the glutamate transporter process that mapped to a chromosome (5p12) noted in multiple ADHD genome scans.[52]

Further mutations to four different metabotropic glutamate receptor genes were identified in a study of 1013 children with ADHD compared to 4105 controls with non-ADHD, replicated in a subsequent study of 2500 more patients. Deletions and duplications affected GRM1, GRM5, GRM7 and GRM8. The study concluded that “CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9)”, “over 200 genes interacting with glutamate receptors [. .] were collectively affected by CNVs”, “major hubs of the (affected genes’) network include TNIK50, GNAQ51, and CALM”, and “the fact that children with ADHD are more likely to have alterations in these genes reinforces previous evidence that the GRM pathway is important in ADHD”.[47]

A SciBX article in January 2012 commented that “UPenn and MIT teams have independently converged on mGluRs as players in ADHD and autism. The findings suggest agonizing mGluRs in patients with ADHD”.[53]

Autism

The etiology of autism may include excessive glutamatergic mechanisms. In small studies, memantine has been shown to significantly improve language function and social behavior in children with autism.[54][55] Research is underway on the effects of memantine in adults with autism spectrum disorders.[56]

A link between glutamate receptors and autism was also identified via the structural protein ProSAP1 SHANK2 and potentially ProSAP2 SHANK3. The study authors concluded that the study “illustrates the significant role glutamatergic systems play in autism” and “By comparing the data on ProSAP1/Shank2−/− mutants with ProSAP2/Shank3αβ−/− mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.”[48]

Diabetes

Diabetes is a peculiar case because it is influenced by glutamate receptors present outside of the central nervous system, and it also influences glutamate receptors in the central nervous system.

Diabetes mellitus, an endocrine disorder, induces cognitive impairment and defects of long-term potential in the hippocampus, interfering with synaptic plasticity. Defects of long-term potential in the hippocampus are due to abnormal glutamate receptors, to be specific the malfunctioning NMDA glutamate receptors during early stages of the disease.[57]

Research is being done to address the possibility of using hyperglycemia and insulin to regulate these receptors and restore cognitive functions. Pancreatic islets regulating insulin and glucagon levels also express glutamate receptors.[27] Treating diabetes via glutamate receptor antagonists is possible, but not much research has been done. The difficulty of modifying peripheral GluR without having detrimental effects on the central nervous system, which is saturated with GluR, may be the cause of this.

Huntington’s disease

In 2004, a specific genotype of human GluR6 was discovered to have a slight influence on the age of onset of Huntington’s disease.[58]

In addition to similar mechanisms causing Parkinson’s disease with respect to NMDA or AMPA receptors, Huntington’s disease was also proposed to exhibit metabolic and mitochondrial deficiency, which exposes striatal neurons to the over activation of NMDA receptors.[37] Using folic acid has been proposed as a possible treatment for Huntington’s due to the inhibition it exhibits on homocysteine, which increases vulnerability of nerve cells to glutamate.[59] This could decrease the effect glutamate has on glutamate receptors and reduce cell response to a safer level, not reaching excitotoxicity.

Ischemia

During ischemia, the brain has been observed to have an unnaturally high concentration of extracellular glutamate.[60] This is linked to an inadequate supply of ATP, which drives the glutamate transport levels that keep the concentrations of glutamate in balance.[61] This usually leads to an excessive activation of glutamate receptors, which may lead to neuronal injury. After this overexposure, the postsynaptic terminals tend to keep glutamate around for long periods of time, which results in a difficulty in depolarization.[61] Antagonists for NMDA and AMPA receptors seem to have a large benefit, with more aid the sooner it is administered after onset of the neural ischemia.[37]

Multiple sclerosis

Inducing experimental autoimmune encephalomyelitis in animals as a model for multiple sclerosis(MS) has targeted some glutamate receptors as a pathway for potential therapeutic applications.[62] This research has found that a group of drugs interact with the NMDA, AMPA, and kainate glutamate receptor to control neurovascular permeability, inflammatory mediator synthesis, and resident glial cell functions including CNS myelination. Oligodendrocytes in the CNS myelinate axons; the myelination dysfunction in MS is partly due to the excitotoxicity of those cells. By regulating the drugs which interact with those glutamate receptors, regulating glutamate binding may be possible, and thereby reduce the levels of Ca2+ influx. The experiments showed improved oligodendrocyte survival, and remyelination increased. Furthermore, CNS inflammation, apoptosis, and axonal damage were reduced.[62]

Parkinson’s disease (Parkinsonism)

Late onset neurological disorders, such as Parkinson’s disease, may be partially due to glutamate binding NMDA and AMPA glutamate receptors.[37] In vitro spinal cord cultures with glutamate transport inhibitors led to degeneration of motor neurons, which was counteracted by some AMPA receptor antagonists such as GYKI 52466.[37] Research also suggests that the metabotropic glutamate receptor mGlu4 is directly involved in movement disorders associated with the basal ganglia through selectively modulating glutamate in the striatum.[63]

Rasmussen’s encephalitis

In 1994, GluR3 was shown to act as an autoantigen in Rasmussen’s encephalitis, leading to speculation that autoimmune activity might underlie the condition.[33]

Schizophrenia

In schizophrenia, the expression of the mRNA for the NR2A subunit of the NMDA glutamate receptor was found to be decreased in a subset of inhibitory interneurons in the cerebral cortex.[64] This is suggested by upregulation of GABA, an inhibitory neurotransmitter. In schizophrenia, the expression of the NR2A subunit of NDMA receptors in mRNA was experimentally undetectable in 49-73% in GABA neurons that usually express it. These are mainly in GABA cells expressing the calcium-buffering protein parvalbumin (PV), which exhibits fast-spiking firing properties and target the perisomatic (basket cells) and axo-axonic (chandelier cells) compartments of pyramidal neurons.[64] The study found the density of NR2A mRNA-expressing PV neurons was decreased by as much as 50% in subjects with schizophrenia. In addition, density of immunohistochemically labeled glutamatergic terminals with an antibody against the vesicular glutamate transporter vGluT1 also exhibited a reduction that paralleled the reduction in the NR2A-expressing PV neurons. Together, these observations suggest glutamatergic innervation of PV-containing inhibitory neurons appears to be deficient in schizophrenia.[64] Expression of NR2A mRNA has also been found to be altered in the inhibitory neurons that contain another calcium buffer, calbindin, targeting the dendrites of pyramidal neurons,[65] and the expression of the mRNA for the GluR5 kainate receptor in GABA neurons has also been found to be changed in organisms with schizophrenia.[66] Current research is targeting glutamate receptor antagonists as potential treatments for schizophrenia. Memantine, a weak, nonselective NMDA receptor antagonist, was used as an add-on to clozapine therapy in a clinical trial. Refractory schizophrenia patients showed associated improvements in both negative and positive symptoms, underscoring the potential uses of GluR antagonists as antipsychotics.[67] Furthermore, administration of noncompetitive NMDA receptor antagonists have been tested on rat models. Scientists proposed that specific antagonists can act on GABAergic interneurons, enhancing cortical inhibition and preventing excessive glutamatergic transmission associated with schizophrenia. These and other atypical antipsychotic drugs can be used together to inhibit excessive excitability in pyramidal cells, decreasing the symptoms of schizophrenia.[68]

Seizures

Glutamate receptors have been discovered to have a role in the onset of epilepsy. NMDA and metabotropic types have been found to induce epileptic convulsions. Using rodent models, labs have found that the introduction of antagonists to these glutamate receptors helps counteract the epileptic symptoms.[69] Since glutamate is a ligand for ligand-gated ion channels, the binding of this neurotransmitter will open gates and increase sodium and calcium conductance. These ions play an integral part in the causes of seizures. Group 1 metabotropic glutamate receptors (mGlu1 and mGlu5) are the primary cause of seizing, so applying an antagonist to these receptors helps in preventing convulsions.[70]

Other diseases suspected of glutamate receptor link

Neurodegenerative diseases with a suspected excitotoxicity link

Neurodegenerative diseases suspected to have a link mediated (at least in part) through stimulation of glutamate receptors:[35][71]

• AIDS dementia complex *
• Alzheimer’s disease *
• Amyotrophic lateral sclerosis
• Combined systems disease (vitamin B12 deficiency)
• Depression/anxiety *
• Drug addiction, tolerance, and dependency *
• Glaucoma
• Hepatic encephalopathy
• Hydroxybutyric aminoaciduria
• Hyperhomocysteinemia and homocysteinuria
• Hyperprolinemia
• Lead encephalopathy
• Leber’s disease
• MELAS syndrome
• MERRF
• Mitochondrial abnormalities (and other inherited or acquired biochemical disorders)
• Neuropathic pain syndromes (e.g. causalgia or painful peripheral neuropathies)
• Nonketotic hyperglycinemia
• Olivopontocerebellar atrophy (some recessive forms)
• Essential tremor
• Rett syndrome
• Sulfite oxidase deficiency
• Wernicke’s encephalopathy

 

Synapse signaler: Small Cell Receptors: NUNZIA ia a Blocker

With California Biotech’s NUNZIA drug being able to block the cause of ANXIETY in the area of the brain that deals with the following:

• Forming new memories and connecting emotions and senses, such as smell and sound, to memories
• Consolidation of new memory
• Emotional Responses
• Navigation
• Spatial Orientation

NUNZIA works with the Hippocampus part of the brain.

Mayo Clinic Staff, (www.Maycoclinic.com.. OCD)

Annu Rev Psychol. Author manuscript; available in PMC 2010 Dec 30. PMCID: PMC3012424

NIHMSID: NIHMS259849

Published in final edited form as:

Annu Rev Psychol. 2010; 61: 111–C3.

doi: 10.1146/annurev.psych.093008.100359

Structural Plasticity and Hippocampal Function

Benedetta Leuner and Elizabeth Gould

Author information ► Copyright and License information ►

The publisher’s final edited version of this article is available at Annu Rev Psychol

See other articles in PMC that cite the published article.

Abstract

NUNZIA works with the Hippocampus part of the brain.

The hippocampus is a region of the mammalian brain that shows an impressive capacity for structural reorganization. Preexisting neural circuits undergo modifications in dendritic complexity and synapse number, and entirely novel neural connections are formed through the process of neurogenesis. These types of structural change were once thought to be restricted to development. However, it is now generally accepted that the hippocampus remains structurally plastic throughout life. This article reviews structural plasticity in the hippocampus over the lifespan, including how it is investigated experimentally. The modulation of structural plasticity by various experiential factors as well as the possible role it may have in hippocampal functions such as learning and memory, anxiety, and stress regulation are also considered. Although significant progress has been made in many of these areas, we highlight some of the outstanding issues that remain.

Keywords: adult neurogenesis, anxiety, learning, memory, synapse

Regressive events also sculpt hippocampal circuitry during development—pruning of dendritic branches occurs on the granule cells during this time (Rahimi & Claiborne 2007). Similar events occur throughout the hippocampus—postnatal development of dendritic arbors and the formation of dendritic spines followed by dendritic pruning and synapse elimination are also features of the pyramidal neuron population (Liu et al. 2005).

(A, B) Photomicrographs of newly born neurons (arrows) in the dentate gyrus of an adult rat labeled with BrdU (red) coexpressing (A) NeuN (green), a marker of mature neurons or (B) TuJ1 (green), a marker of immature and mature neurons. Scale bars, 10 …

Negative Versus Positive Stress

Stressors are typically defined in terms of their ability to activate the hypothalamic-pituitary-adrenal (HPA) axis and ultimately increase glucocorticoid levels (reviewed in Ulrich-Lai & Herman 2009). Most experiences known to cause HPA axis activation are aversive. Exposure to aversive stressors adversely influences numerous aspects of hippocampal structure.

With few exceptions (Bain et al. 2004, Snyder et al. 2009a, Thomas et al. 2007), new cell production in the dentate gyrus is inhibited by a variety of acute and chronic aversive experiences, including both physical and psychosocial stressors (reviewed in Mirescu & Gould 2006). Stress-induced suppression of cell proliferation has been demonstrated in various species (mouse, rat, tree shrew, monkey) and occurs throughout life, with similar results reported for the early postnatal period, young adulthood, and aging (Coe et al. 2003; Gould et al. 1997, 1998; Simon et al. 2005; Tanapat et al. 1998, 2001; Veenema et al. 2007). When stressor exposure occurs during development, the effects are enduring and can persist into adulthood (Lemaire et al. 2000, Lucassen et al. 2009, Mirescu et al. 2004). However, it is unclear whether stress experienced in adulthood has a long-lasting influence on hippocampal neurogenesis. Prolonged effects of stress on new neuron production (Heine et al. 2004, Malberg & Duman 2003, Pham et al. 2003) and survival (Koo & Duman 2008, Thomas et al. 2007, Westenbroek et al. 2004) have been observed. Yet, others have shown that the influence of stress on adult neurogenesis is temporary, decreasing cell proliferation and immature neuron production without altering the number of new neurons that survive to maturity (Mirescu et al. 2004, Snyder et al. 2009a, Tanapat et al. 2001). The reason for these discrepancies is unknown but may be related to the duration or intensity of the stressor or timing of BrdU labeling or sacrifice relative to the stressful experience.

In addition to suppressing neurogenesis, aversive stressful experiences alter dendritic architecture in the hippocampus. For example, repeated stress in adulthood induces retraction of CA3 pyramidal neuron dendrites as well as a loss of synapses in adult male rats and tree shrews (Magariños et al. 1996, McKittrick et al. 2000, Stewart et al. 2005). Within hours of stressor onset, dendritic spine density in the CA3 region is also reduced (Chen et al. 2008). The effects of stress on dendritic architecture in other hippocampal regions have been less well-studied. Chronic stress causes dendritic regression and spine synapse loss in the dentate gyrus and CA1 (Hajszan et al. 2009, Sousa et al. 2000). Acute stress also alters dendritic spine density on CA1 pyramidal cells of adult rats, but the direction of the effect is dependent on the sex of the animal, increasing the number of dendritic spines in males but decreasing the number of dendritic spines in females (Shors et al. 2001a).

Some evidence demonstrates that glucocorticoids regulate structural plasticity in the hippocampus and are the primary mediator underlying the detrimental effects of aversive stress on hippocampal structure. First, an inhibition of neurogenesis occurs in response to natural changes in glucocorticoids across the lifespan. Neurogenesis in the dentate gyrus is maximal during the early postnatal period, when levels of circulating glucocorticoids are low (Gould et al. 1991b) but diminished during life stages when glucocorticoids are elevated, including aging and the postpartum period (Cameron & McKay 1999; Kuhn et al. 1996; Leuner et al. 2007a,b). Second, glucocorticoid administration during the early postnatal period and in adulthood suppresses neurogenesis (Cameron & Gould 1994, Gould et al. 1991b). Conversely, removal of circulating glucocorticoids by bilateral adrenalectomy increases neurogenesis in adult and aged rats (Cameron & Gould 1994, Cameron & McKay 1999) and prevents the stress-induced reduction in neurogenesis (Mirescu et al. 2004, Tanapat et al. 2001). Third, blocking glucocorticoid receptors can reverse the reduction in neurogenesis after glucocorticoid treatment (Mayer et al. 2006) or stressor exposure (Oomen et al. 2007). Like neurogenesis, the stress-induced atrophy of CA3 pyramidal neurons is prevented by pharmacological blockade of the glucocorticoid stress response and can be mimicked by exogenous glucocorticoid administration (Magariños & McEwen 1995, Woolley et al. 1990b).

Physical Activity :

It is becoming increasingly clear, however, that glucocorticoids are not the sole factor mediating the suppressive action of stress on hippocampal structure (Gould et al. 1997, Koo & Duman 2008, Van der Borght et al. 2005a) and that the effects of glucocorticoids on structural plasticity are complex. Notably, conditions associated with elevated glucocorticoids do not necessarily have detrimental effects on structural plasticity and in some cases, those conditions can be beneficial. Physical activity is an example of this paradox—despite substantial elevations in circulating glucocorticoids, running enhances adult neurogenesis (Stranahan et al. 2006, van Praag et al. 1999, Zhao et al. 2006) and dendritic architecture (Eadie et al. 2005, Stranahan et al. 2007) in the hippocampus.

Learning:

This effect persists until the new neurons are at least two months old (Leuner et al. 2004). Other hippocampus-dependent tasks, such as long-delay eye blink conditioning, as well as spatial learning in the Morris water maze and conditioned food preference, also increase the number of newborn cells. (Ambrogini et al. 2000, Döbrössy et al. 2003, Dupret et al. 2007, Gould et al. 1999b, Hairston et al. 2005, Lemaire et al. 2000, Leuner et al. 2006a, Olariu et al. 2005).

In addition to differences in BrdU injection protocols and training paradigms employed, the maturity of the labeled adult-born cells at the time of learning may determine whether and how learning alters them. Both spatial learning and trace eyeblink conditioning encourage the survival of new cells born about one week prior to training, when these cells are immature but already differentiated into neurons (Ambrogini et al. 2000, Dupret et al. 2007, Epp et al. 2007, Gould et al. 1999b, Hairston et al. 2005). In contrast, some studies suggest that spatial learning induces the death of cells that are less mature (i.e., ≤4 days of age; Dupret et al. 2007, Mohapel et al. 2006), whereas others show that the death of older and perhaps more mature cells occurs (i.e., ≥10 days of age; Ambrogini et al. 2004). Therefore, learning may have a differential capacity to influence neurogenesis depending on the age of the cell. This is consistent with observations showing that experience-induced modulation of adult neurogenesis occurs at a critical period during an immature stage (Tashiro et al. 2007).

The purpose of a learning-induced enhancement of neurogenesis remains to be fully determined. One possibility is that these newborn neurons can contribute to learning and memory by creating a neural representation of previous experience (Aimone et al. 2009). Work showing that neurons made to survive by exposure to an enriched environment are preferentially activated at a later time to the same, but not a different, experience lends some support to the possibility that such a process takes place (Tashiro et al. 2007).

Experimental Approaches to Study the Role of Structural Plasticity in Hippocampal Function

Several strategies have been used to link structural change to hippocampal function. One is correlative and involves evaluating whether there is a positive relationship between structural plasticity and hippocampal function. Another is more direct and involves blocking structural changes and examining whether hippocampal functions are altered. With respect to adult neurogenesis, the depletion of newborn cells has been achieved pharmacologically by systemic administration of the antimitotic agent methylazoxymethanol (MAM; Bruel-Jungerman et al. 2005, Shors et al. 2001b) or the DNA-alkylating agent temozolomide (TMZ; Garthe et al. 2009) as well as by central infusion of the mitotic blocker cytosine arabinoside (AraC; Mak et al. 2007). However, none of these agents diminish the number of newborn neurons exclusively within the dentate gyrus. Irradiation is another approach to block hippocampal neurogenesis and when applied focally, spares neurogenesis in the rest of the brain (Clelland et al. 2009, Santarelli et al. 2003, Saxe et al. 2006, Winocur et al. 2006). One downside common to all of these methods is their nonspecific side effects that may complicate the interpretation of results (Dupret et al. 2005, Monje et al. 2003). Genetic ablation of dividing progenitors may be less susceptible to this criticism, but again assessing behavioral consequences is difficult because inhibition of the dividing precursors is not restricted to the dentate gyrus (Garcia et al. 2004, Saxe et al. 2006). For this reason, virus-based strategies have been developed to prevent neurogenesis exclusively in the dentate gyrus at a specific time in adulthood (Clelland et al. 2009, Jessberger et al. 2009). However, the possibility that postmitotic neurons are affected by the virus and may contribute to behavioral alterations cannot be ruled out. Most recently, inducible genetic approaches to ablate specific populations of adult-generated neurons in a temporally and spatially precise manner have been used (Imayoshi et al. 2008, Revest et al. 2009, Zhang et al. 2008), although these too are not without practical drawbacks.

A Possible Role in Learning and Memory

The role of the hippocampus in learning and memory has long been recognized. However, the hippocampus has been associated with a range of learning tasks (e.g., trace conditioning, contextual fear conditioning, social transmission of food preference, spatial navigation, and object recognition, to name a few) that do not readily fall into a single category, making a unifying theory of hippocampal function difficult to pin down. One reason for this may be related to findings from recent studies incorporating a subregional analysis of the hippocampus that suggests a heterogeneous distribution of function within its different subfields (reviewed in Rolls & Kesner 2006) as well as along the septotemporal axis (reviewed in Bannerman et al. 2004, Moser & Moser 1998). Despite this complexity, it has been proposed that learning and memory might require structural changes in the hippocampus (reviewed in Lamprecht & LeDoux 2004, Nottebohm 2002). In support of this, numerous positive correlations between learning and structural plasticity have been demonstrated.

In rodents, a variety of conditions that decrease adult neurogenesis in the dentate gyrus are associated with learning impairments. These include stress, increased levels of circulating glucocorticoids, and aging (Drapeau et al. 2003, Montaron et al. 2006). Similarly, adverse prenatal or early-life experiences produce persistent reductions in neurogenesis and reduced learning abilities in adulthood (Lemaire et al. 2000). Conversely, conditions that increase neurogenesis, such as environmental enrichment and physical exercise, also tend to enhance performance on hippocampal-dependent learning tasks (Kempermann et al. 1997; van Praag et al. 1999, 2005). There are also a number of studies that have found no correlation or even a negative correlation between neurogenesis and learning (reviewed in Leuner et al. 2006b). However, it is important to keep in mind that a positive correlation between the number of new neurons and learning performance implies a relationship between neurogenesis and learning, although not necessarily a causal one. Another issue to consider is that the time course for alterations in cell production may not correspond to changes in learning abilities. For example, it seems unlikely that the production of new cells would have an immediate effect on processes involved in learning because the cells probably require a certain level of differentiation to have an impact on behavior. Perhaps an even more important consideration, and one that is impossible to discount, is the fact that many of the factors known to affect neurogenesis alter other aspects of brain structure, such as dendritic architecture and synapse number. Since these types of changes are also likely to be involved in hippocampal-dependent learning, it is difficult to interpret correlations between new neurons and learning.

Because of the caveats associated with correlative studies, other work has attempted to demonstrate a casual relationship between learning and neurogenesis, but these too have yielded mixed findings (Leuner et al. 2006b). Reducing or blocking hippocampal neurogenesis disrupts various hippocampal-dependent forms of learning and memory (Clelland et al. 2009; Dupret et al. 2008; Garthe et al. 2009; Hernandez-Rabaza et al. 2009; Jessberger et al. 2009; Imayoshi et al. 2008; Madsen et al. 2003; Raber et al. 2004; Rola et al. 2004; Saxe et al. 2006; Shors et al. 2001b, 2002; Snyder et al. 2005; Winocur et al. 2006; Zhang et al. 2008). Recent findings further suggest that the correct differentiation and integration of new neurons may be necessary for acquisition of new information and the recall of memories consolidated in tasks previously performed (Farioli-Vecchioli et al. 2008). However, a large number of studies have failed to demonstrate an involvement of newly generated cells in hippocampal-dependent learning (Hernandez-Rabaza et al. 2009, Jessberger et al. 2009, Shors et al. 2002, Snyder et al. 2005, Zhang et al. 2008), and there is at least one demonstration of enhanced learning following the suppression of neurogenesis (Saxe et al. 2007). These discrepancies can be attributed to numerous factors, including the animal species and strain tested and the method of ablation, as well as the specifics of the design, analysis, and interpretation of the learning paradigm employed (Garthe et al. 2009).

REFERENCES

1. Ackman JB, Siddiqi F, Walikonis RS, LoTurco JJ. Fusion of microglia with pyramidal neurons after retroviral infection. J. Neurosci. 2006;26:11413–22. [PubMed]

2. Aimone JB, Wiles J, Gage FH. Computational influence of adult neurogenesis on memory encoding. Neuron. 2009;61:187–202. [PMC free article] [PubMed]

3. Airan RD, Meltzer LA, Roy M, Gong Y, Chen H, Deisseroth K. High-speed imaging reveals neuro-physiological links to behavior in an animal model of depression. Science. 2007;317:819–23. [PubMed]

4. Altman J. Are new neurons formed in the brains of adult mammals? Science. 1962;135:1127–28. [PubMed]

5. Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. 1965;124:319–35. [PubMed]

6. Ambrogini P, Cuppini R, Cuppini C, Ciaroni S, Cecchini T, et al. Spatial learning affects immature granule cell survival in the adult dentate gyrus. Neurosci. Lett. 2000;286:21–24. [PubMed]

7. Ambrogini P, Orsini L, Mancini C, Ferri P, Ciaroni S, Cuppini R. Learning may reduce neurogenesis in the adult rat dentate gyrus. Neurosci. Lett. 2004;359:13–16. [PubMed]

8. Amrein I, Dechmann DK, Winter Y, Lipp HP. Absent or low rate of adult neurogenesis in the hippocampus of bats (Chiroptera) PLoS One. 2007;2:e455. [PMC free article] [PubMed]

9. Amrein I, Slomianka L, Lipp HP. Granule cell number, cell death and cell proliferation in the dentate gyrus of wild-living rodents. Eur. J. Neurosci. 2004;20:3342–50. [PubMed]

10. Andersen P, Soleng AF. Long-term potentiation and spatial training are both associated with the generation of new excitatory synapses. Brain Res. Brain Res. Rev. 1998;26:353–59. [PubMed]

11. Bain MJ, Dwyer SM, Rusak B. Restraint stress affects hippocampal cell proliferation differently in rat and mice. Neurosci. Lett. 2004;368:7–10. [PubMed]

12. Bannerman DM, Rawlins JN, McHugh SB, Deacon RM, Yee BK, et al. Regional dissociations within the hippocampus—memory and anxiety. Neurosci. Biobehav. Rev. 2004;28:273–83. [PubMed]

13. Barnea A, Nottebohm F. Seasonal recruitment of hippocampal neurons in adult free-ranging black-capped chickadees. Proc. Natl. Acad. Sci. USA. 1994;91:11217–21. [PMC free article] [PubMed]

14. Bauer S, Patterson PH. The cell cycle-apoptosis connection revisited in the adult brain. J. Cell Biol. 2005;171:641–50. [PMC free article] [PubMed]

15. Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology. 2009;34:2376–89. [PMC free article] [PubMed]

16. Bonhoeffer T, Yuste R. Spine motility. Phenomenology, mechanisms, and function. Neuron. 2002;35:1019–27. [PubMed]

17. Brené S, Bjørnebekk A, Aberg E, Mathé AA, Olson L, Werme M. Running is rewarding and antidepressive. Physiol. Behav. 2007;92:136–40. [PMC free article] [PubMed]

18. Bruel-Jungerman E, Davis S, Rampon C, Laroche S. Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J. Neurosci. 2006;26:5888–93. [PubMed]

19. Bruel-Jungerman E, Laroche S, Rampon C. New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur. J. Neurosci. 2005;21:513–21. [PubMed]

20. Bull ND, Bartlett PF. The adult mouse hippocampal progenitor is neurogenic but not a stem cell. J. Neurosci. 2005;25:10815–21. [PubMed]

21. Burke SN, Barnes CA. Neural plasticity in the ageing brain. Nat. Rev. Neurosci. 2006;7:30–40. [PubMed]

22. Burns KA, Kuan CY. Low doses of bromo- and iododeoxyuridine produce near-saturation labeling of adult proliferative populations in the dentate gyrus. Eur. J. Neurosci. 2005;21:803–7. [PubMed]

23. Cameron HA, Gould E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience. 1994;61:203–9. [PubMed]

24. Cameron HA, McKay RD. Restoring production of hippocampal neurons in old age. Nat. Neurosci. 1999;2:894–97. [PubMed]

25. Cameron HA, McKay RD. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 2001;435:406–17. [PubMed]

26. Cameron HA, Woolley CS, McEwen BS, Gould E. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience. 1993;56:337–44. [PubMed]

27. Campbell S, MacQueen G. The role of the hippocampus in the pathophysiology of major depression. J. Psychiatry Neurosci. 2004;29:417–26. [PMC free article] [PubMed]

28. Chehrehasa F, Meedeniya ACB, Dwyer P, Abrahamsen G, Mackay-Sim A. EdU, a new thymidine analogue for labeling proliferating cells in the nervous system. J. Neurosci. Methods. 2009;177:122–30. [PubMed]

29. Chen Y, Dubé CM, Rice CJ, Baram TZ. Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone. J. Neurosci. 2008;28:2903–11. [PMC free article] [PubMed]

30. Christie BR, Cameron HA. Neurogenesis in the adult hippocampus. Hippocampus. 2006;16:199–207. [PubMed]

31. Clelland CD, Choi M, Romberg C, Clemenson GD, Jr, Fragniere A, et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009;325:210–13. [PMC free article] [PubMed]

32. Coe CL, Kramer M, Cźeh B, Gould E, Reeves AJ, et al. Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys. Biol. Psychiatry. 2003;54:1025–34. [PubMed]

33. Conrad CD. What is the functional significance of chronic stress-induced CA3 dendritic retraction within the hippocampus? Behav. Cogn. Neurosci. Rev. 2006;5:41–60. [PMC free article] [PubMed]

34. Couillard-Despres S, Winner B, Karl C, Lindemann G, Schmid P, et al. Targeted transgene expression in neuronal precursors: watching young neurons in the old brain. Eur. J. Neurosci. 2006;24:1535–45. [PubMed]

35. Dailey M, Marrs G, Satz J, Waite M. Concepts in imaging and microscopy. Exploring biological structure and function with confocal microscopy. Biol. Bull. 1999;197:115–22. [PubMed]

36. Dalla C, Bangasser DA, Edgecomb C, Shors TJ. Neurogenesis and learning: acquisition and asymptotic performance predict how many new cells survive in the hippocampus. Neurobiol. Learn. Mem. 2007;88:143–48. [PMC free article] [PubMed]

37. Dalla C, Papachristos EB, Whetstone AS, Shors TJ. Female rats learn trace memories better than male rats and consequently retain a greater proportion of new neurons in their hippocampi. Proc. Natl. Acad. Sci. USA. 2009;106:2927–32. [PMC free article] [PubMed]

38. Dayer AG, Ford AA, Cleaver KM, Yassaee M, Cameron HA. Short-term and long-term survival of new neurons in the rat dentate gyrus. J. Comp. Neurol. 2003;460:563–72. [PubMed]

39. de Kloet ER, Vreugdenhil E, Oitzl MS, Joëls M. Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 1998;19:269–301. [PubMed]

40. De Roo M, Klauser P, Garcia PM, Poglia L, Muller D. Spine dynamics and synapse remodeling during LTP and memory processes. Prog. Brain Res. 2008;169:199–207. [PubMed]

41. Döbrössy MD, Drapeau E, Aurousseau C, Le Moal M, Piazza PV, Abrous DN. Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date. Mol. Psychiatry. 2003;8:974–82. [PubMed]

42. Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous DN. Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc. Natl. Acad. Sci. USA. 2003;100:14385–90. [PMC free article] [PubMed]

43. Dupret D, Fabre A, Döbrössy MD, Panatier A, Rodríguez JJ, et al. Spatial learning depends on both the addition and removal of new hippocampal neurons. PLoS Biol. 2007;5:e214. [PMC free article] [PubMed]

44. Dupret D, Montaron MF, Drapeau E, Aurousseau C, Le Moal M, et al. Methylazoxymethanol acetate does not fully block cell genesis in the young and aged dentate gyrus. Eur. J. Neurosci. 2005;22:778–83. [PubMed]

45. Dupret D, Revest JM, Koehl M, Ichas F, De Giorgi F, et al. Spatial relational memory requires hippocampal adult neurogenesis. PLoS ONE. 2008;3:e1959. [PMC free article] [PubMed]

46. Eadie BD, Redila VA, Christie BR. Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density. J. Comp. Neurol. 2005;486:39–47. [PubMed]

47. Ehninger D, Kempermann G. Paradoxical effects of learning the Morris water maze on adult hippocampal neurogenesis in mice may be explained by a combination of stress and physical activity. Genes Brain Behav. 2006;5:29–39. [PubMed]

48. Eisch AJ, Cameron HA, Encinas JM, Meltzer L, Ming GL, Overstreet-Wadiche LS. Adult neurogenesis, mental health, and mental illness: hope or hype? J. Neurosci. 2008;28:11785–91. [PMC free article] [PubMed]

49. Eisch AJ, Mandyam CD. Adult neurogenesis: Can analysis of cell cycle proteins move us “Beyond BrdU”? Curr. Pharm. Biotechnol. 2007;8:147–65. [PubMed]

50. Encinas JM, Vaahtokari A, Enikolopov G. Fluoxetine targets early progenitor cells in the adult brain. Proc. Natl. Acad. Sci. USA. 2006;103:8233–38. [PMC free article] [PubMed]

51. Epp JR, Barker JM, Galea LA. Running wild: neurogenesis in the hippocampus across the lifespan in wild and laboratory-bred Norway rats. Hippocampus. 2009 In press. [PubMed]

52. Epp JR, Spritzer MD, Galea LA. Hippocampus-dependent learning promotes survival of new neurons in the dentate gyrus at a specific time during cell maturation. Neuroscience. 2007;149:273–85. [PubMed]

53. Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, et al. Neurogenesis in the adult human hippocampus. Nat. Med. 1998;4:1313–17. [PubMed]

54. Espósito MS, Piatti VC, Laplagne DA, Morgenstern NA, Ferrari CC, et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J. Neurosci. 2005;25:10074–86. [PubMed]

55. Eyre MD, Richter-Levin G, Avital A, Stewart MG. Morphological changes in hippocampal dentate gyrus synapses following spatial learning in rats are transient. Eur. J. Neurosci. 2003;17:1973–80. [PubMed]

56. Farioli-Vecchioli S, Saraulli D, Costanzi M, Pacioni S, Cinà I, et al. The timing of differentiation of adult hippocampal neurons is crucial for spatial memory. PLoS Biol. 2008;6:e246. [PMC free article] [PubMed]

57. Fiala JC, Feinberg M, Popov V, Harris KM. Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J. Neurosci. 1998;18:8900–11. [PubMed]

58. Flood DG. Critical issues in the analysis of dendritic extent in aging humans, primates, and rodents. Neurobiol. Aging. 1993;14:649–54. [PubMed]

59. Flusberg BA, Nimmerjahn A, Cocker ED, Mukamel EA, Barretto RP. High-speed, miniaturized fluorescence microscopy in freely moving mice. Nat. Methods. 2008;5:935–38. [PMC free article] [PubMed]

60. Frankland PW, Bontempi B. The organization of recent and remote memories. Nat. Rev. Neurosci. 2005;6:119–30. [PubMed]

61. Garcia AD, Doan NB, Imura T, Bush TG, Sofroniew MV. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat. Neurosci. 2004;7:1233–41. [PubMed]

62. Garthe A, Behr J, Kempermann G. Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies. PLoS One. 2009;5:e5464. [PMC free article] [PubMed]

63. Ge S, Goh EL, Sailor KA, Kitabatake Y, Ming GL, Song H. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature. 2006;439:589–93. [PMC free article] [PubMed]

64. Ge S, Yang CH, Hsu KS, Ming GL, Song H. A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron. 2007;54:559–66. [PMC free article] [PubMed]

65. Geinisman Y, Berry RW, Disterhoft JF, Power JM, Van Der Zee EA. Associative learning elicits the formation of multiple-synapse boutons. J. Neurosci. 2001;21:5568–73. [PubMed]

66. Geinisman Y, deToledo-Morrell L, Morrell F, Persina IS, Rossi M. Age-related loss of axospinous synapses formed by two afferent systems in the rat dentate gyrus as revealed by the unbiased stereological dissector technique. Hippocampus. 1992;2:437–44. [PubMed]

67. Gheusi G, Ortega-Perez I, Murray K, Lledo PM. A niche for adult neurogenesis in social behavior. Behav. Brain Res. 2009;200:315–22. [PubMed]

68. Globus A, Rosenzweig MR, Bennett EL, Diamond MC. Effects of differential experience on dendritic spine counts in rat cerebral cortex. J. Comp. Physiol. Psychol. 1973;82:175–81. [PubMed]

69. Gould E. How widespread is adult neurogenesis in mammals? Nat. Rev. Neurosci. 2007;8:481–88. [PubMed]

70. Gould E, Beylin A, Tanapat P, Reeves AJ, Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat. Neurosci. 1999b;2:260–65. [PubMed]

71. Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 1997;17:2492–98. [PubMed]

72. Gould E, Reeves AJ, Fallah M, Tanapat P, Gross CG, Fuchs E. Hippocampal neurogenesis in adult Old World primates. Proc. Natl. Acad. Sci. USA. 1999a;96:5263–67. [PMC free article] [PubMed]

73. Gould E, Tanapat P. Lesion-induced proliferation of neuronal progenitors in the dentate gyrus of the adult rat. Neuroscience. 1997;80:427–36. [PubMed]

74. Gould E, Tanapat P, McEwen BS, Flügge G, Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc. Natl. Acad. Sci. USA. 1998;95:3168–71. [PMC free article] [PubMed]

75. Gould E, Vail N, Wagers M, Gross CG. Adult-generated hippocampal and neocortical neurons in macaques have a transient existence. Proc. Natl. Acad. Sci. USA. 2001;98:10910–17. [PMC free article] [PubMed]

76. Gould E, Woolley CS, Cameron HA, Daniels DC, McEwen BS. Adrenal steroids regulate postnatal development of the rat dentate gyrus: II. Effects of glucocorticoids and mineralocorticoids on cell birth. J. Comp. Neurol. 1991b;313:486–93. [PubMed]

77. Gould E, Woolley CS, McEwen BS. Naturally occurring cell death in the developing dentate gyrus of the rat. J. Comp. Neurol. 1991a;304:408–18. [PubMed]

78. Hairston IS, Little MT, Scanlon MD, Barakat MT, Palmer TD, et al. Sleep restriction suppresses neurogenesis induced by hippocampus-dependent learning. J. Neurophysiol. 2005;94:4224–33. [PubMed]

79. Hajszan T, Dow A, Warner-Schmidt JL, Szigeti-Buck K, Sallam NL, et al. Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression. Biol. Psychiatry. 2009;65:392–400. [PMC free article] [PubMed]

80. Hancock A, Priester C, Kidder E, Keith JR. Does 5-bromo-2′-deoxyuridine (BrdU) disrupt cell proliferation and neuronal maturation in the adult rat hippocampus in vivo? Behav. Brain Res. 2009;199:218–21. [PMC free article] [PubMed]

81. Hastings N, Gould E. Rapid extension of axons into the CA3 region by adult-generated granule cells. J. Comp. Neurol. 1999;413:146–54. [PubMed]

82. Hastings NB, Seth MI, Tanapat P, Rydel TA, Gould E. Granule neurons generated during development extend divergent axon collaterals to hippocampal area CA3. J. Comp. Neurol. 2002;452:324–33. [PubMed]

83. He J, Crews FT. Neurogenesis decreases during brain maturation from adolescence to adulthood. Pharmacol. Biochem. Behav. 2007;86:327–33. [PubMed]

84. Heine V, Maslam S, Zareno J, Joëls M, Lucassen PJ. Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible. Eur. J. Neurosci. 2004;19:131–44. [PubMed]

85. Hernández-Rabaza V, Llorens-Martín M, Velázquez-Sánchez C, Ferragud A, Arcusa A, et al. Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal. Neuroscience. 2009;159:59–68. [PubMed]

86. Hodes GE, Yang L, VanKooy J, Santollo J, Shors TJ. Prozac during puberty: distinctive effects on neurogenesis as a function of age and sex. Neuroscience. 2009;163:609–17. [PMC free article] [PubMed]

87. Holick KA, Lee DC, Hen R, Dulawa SC. Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology. 2008;33:406–17. [PubMed]

88. Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, et al. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat. Neurosci. 2008;11:1153–61. [PubMed]

89. Jacobson L, Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr. Rev. 1991;12:118–34. [PubMed]

90. Jessberger S, Aigner S, Clemenson GD, Jr, Toni N, Lie DC, et al. Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus. PLoS Biol. 2008b;6:e272. [PMC free article] [PubMed]

91. Jessberger S, Clark RE, Broadbent NJ, Clemson GD, Jr, Consiglio A, et al. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn. Mem. 2009;16:147–54. [PMC free article] [PubMed]

92. Jessberger S, Toni N, Clemenson GD, Jr, Ray J, Gage FH. Directed differentiation of hippocampal stem/progenitor cells in the adult brain. Nat. Neurosci. 2008a;11:888–93. [PMC free article] [PubMed]

93. Jin K, Wang X, Xie L, Mao XO, Zhu W, et al. Evidence for stroke-induced neurogenesis in the human brain. Proc. Natl. Acad. Sci. USA. 2006;103:13198–202. [PMC free article] [PubMed]

94. Kaplan MS, Hinds JW. Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science. 1977;197:1092–94. [PubMed]

95. Karten YJ, Jones MA, Jeurling SI, Cameron HA. GABAergic signaling in young granule cells in the adult rat and mouse dentate gyrus. Hippocampus. 2006;16:312–20. [PubMed]

96. Kee N, Sivalingam S, Boonstra R, Wojtowicz JM. The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis. J. Neurosci. Methods. 2002;115:97–105. [PubMed]

97. Kee N, Teixeira CM, Wang AH, Frankland PW. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat. Neurosci. 2007;10:355–62. [PubMed]

98. Kempermann G, Jessberger S, Steiner B, Kronenberg G. Milestones of neuronal development in the adult hippocampus. Trends Neuroci. 2004;27:447–52. [PubMed]

99. Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997;386:493–95. [PubMed]

100. Kempermann G, Kuhn HG, Gage FH. Experience-induced neurogenesis in the senescent dentate gyrus. J. Neurosci. 1998;18:3206–12. [PubMed]

101. Klempin F, Kempermann G. Adult hippocampal neurogenesis and aging. Eur. Arch. Psychiatry Clin. Neurosci. 2007;257:271–80. [PubMed]

102. Knafo S, Ariav G, Barkai E, Libersat F. Olfactory learning-induced increase in spine density along the apical dendrites of CA1 hippocampal neurons. Hippocampus. 2004;14:819–25. [PubMed]

103. Koo JW, Duman RS. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Natl. Acad. Sci. USA. 2008;105:751–56. [PMC free article] [PubMed]

104. Kozorovitskiy Y, Gould E. Dominance hierarchy influences adult neurogenesis in the dentate gyrus. J. Neurosci. 2004;24:6755–59. [PubMed]

105. Kozorovitskiy Y, Gross CG, Kopil C, Battaglia L, McBreen M, et al. Experience induces structural and biochemical changes in the adult primate brain. Proc. Natl. Acad. Sci. USA. 2005;102:17478–82. [PMC free article] [PubMed]

106. Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 1996;16:2027–33. [PubMed]

107. Lagace DC, Benavides DR, Kansy JW, Mapelli M, Greengard P, et al. Cdk5 is essential for adult hippocampal neurogenesis. Proc. Natl. Acad. Sci. USA. 2008;105:18567–71. [PMC free article] [PubMed]

108. Lamprecht R, LeDoux J. Structural plasticity and memory. Nat. Rev. Neurosci. 2004;5:45–54. [PubMed]

109. Laplagne DA, Espósito MS, Piatti VC, Morgenstern NA, Zhao C, et al. Functional convergence of neurons generated in the developing and adult hippocampus. PLoS Biol. 2006;4:e409. [PMC free article] [PubMed]

110. Law AJ, Weickert CS, Hyde TM, Kleinman JE, Harrison PJ. Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines. Am. J. Psychiatry. 2004;161:1848–55. [PubMed]

111. Lemaire V, Koehl M, LeMoal M, Abrous DN. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc. Natl. Acad. Sci. USA. 2000;97:11032–37. [PMC free article] [PubMed]

112. Leonardo ED, Richardson-Jones JW, Sibille E, Kottman A, Hen R. Molecular heterogeneity along the dorsal-ventral axis of the murine hippocampal CA1 field: a microarray analysis of gene expression. Neuroscience. 2006;137:177–86. [PubMed]

113. Leuner B, Falduto J, Shors TJ. Associative memory formation increases the observation of dendritic spines in the hippocampus. J. Neurosci. 2003;23:659–65. [PMC free article] [PubMed]

114. Leuner B, Glasper ER, Gould E. Thymidine analog methods for studies of adult neurogenesis are not equally sensitive. J. Comp. Neurol. 2009;517:123–33. [PMC free article] [PubMed]

115. Leuner B, Gould E, Shors TJ. Is there a link between adult neurogenesis and learning? Hippocampus. 2006b;16:216–24. [PubMed]

116. Leuner B, Kozorovitskiy Y, Gross CG, Gould E. Diminished adult neurogenesis in the marmoset brain precedes old age. Proc. Natl. Acad. Sci. USA. 2007a;104:17169–73. [PMC free article] [PubMed]

117. Leuner B, Mendolia-Loffredo S, Kozorovitskiy Y, Samburg D, Gould E, Shors TJ. Learning enhances the survival of new neurons beyond the time when the hippocampus is required for memory. J. Neurosci. 2004;24:7477–81. [PMC free article] [PubMed]

118. Leuner B, Mirescu C, Noiman L, Gould E. Maternal experience inhibits the production of immature neurons in the hippocampus during the postpartum period through elevations in adrenal steroids. Hippocampus. 2007b;17:434–42. [PubMed]

119. Leuner B, Waddell J, Gould E, Shors TJ. Temporal discontiguity is neither necessary nor sufficient for learning-induced effects on adult neurogenesis. J. Neurosci. 2006a;26:13437–42. [PMC free article] [PubMed]

120. Liu XB, Low LK, Jones EG, Cheng HJ. Stereotyped axon pruning via plexin signaling is associated with synaptic complex elimination in the hippocampus. J. Neurosci. 2005;25:9124–34. [PubMed]

121. Lucassen PJ, Bosch OJ, Jousma E, Krömer SA, Andrew R, et al. Prenatal stress reduces postnatal neurogenesis in rats selectively bred for high, but not low, anxiety: possible key role of placental 11bet-ahydroxysteroid dehydrogenase type 2. Eur. J. Neurosci. 2009;29:97–103. [PubMed]

122. Madsen TM, Kristjansen PEG, Bolwig TG, Wortwein G. Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience. 2003;119:635–42. [PubMed]

123. Magariños AM, McEwen BS. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience. 1995;69:89–98. [PubMed]

124. Magariños AM, McEwen BS, Flügge G, Fuchs E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J. Neurosci. 1996;16:3534–40. [PubMed]

125. Mak G, Enwere EK, Gregg C, Pakarainen T, Poutanen M, et al. Male-pheromone-stimulated neurogenesis in the adult female brain: possible role in mating behavior. Nat. Neurosci. 2007;10:1003–11. [PubMed]

126. Malberg JE, Duman RS. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology. 2003;28:1562–71. [PubMed]

127. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 2000;20:9104–10. [PubMed]

128. Manganas LN, Zhang X, Li Y, Hazel RD, Smith SD, et al. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science. 2007;318:980–85. [PMC free article] [PubMed]

129. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat. Med. 2001;7:541–47. [PubMed]

130. Markakis E, Gage F. Adult-generated neurons in the dentate gyrus send axonal projections to field CA3 and are surrounded by synaptic vesicles. J. Comp. Neurol. 1999;406:449–60. [PubMed]

131. Mayer JL, Klumpers L, Maslam S, de Kloet ER, Joëls M, Lucassen PJ. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalises the corticosterone-induced reduction of adult hippocampal neurogenesis. J. Neuroendocrinol. 2006;18:629–31. [PubMed]

132. McEwen BS. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism. 2005;54:20–23. [PubMed]

133. McKittrick CR, Magariños AM, Blanchard DC, Blanchard RJ, McEwen BS, Sakai RR. Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites. Synapse. 2000;36:85–94. [PubMed]

134. Miranda R, Blanco E, Begega A, Santín LJ, Arias JL. Reversible changes in hippocampal CA1 synapses associated with water maze training in rats. Synapse. 2006;59:177–81. [PubMed]

135. Mirescu C, Gould E. Stress and adult neurogenesis. Hippocampus. 2006;16:233–38. [PubMed]

136. Mirescu C, Peters JD, Gould E. Early life experience alters response of adult neurogenesis to stress. Nat. Neurosci. 2004;7:841–46. [PubMed]

137. Mizrahi A, Crowley JC, Shtoyerman E, Katz LC. High-resolution in vivo imaging of hippocampal dendrites and spines. J. Neurosci. 2004;24:3147–51. [PubMed]

138. Mohapel P, Mundt-Petersen K, Brundin P, Frielingsdorf H. Working memory training decreases hippocampal neurogenesis. Neuroscience. 2006;142:609–13. [PubMed]

139. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302:1760–65. [PubMed]

140. Montaron MF, Drapeau E, Dupret D, Kitchener P, Aurousseau C, et al. Lifelong corticosterone level determines age-related decline in neurogenesis and memory. Neurobiol. Aging. 2006;27:645–54. [PubMed]

141. Morgenstern NA, Lombardi G, Schinder AF. Newborn granule cells in the ageing dentate gyrus. J. Physiol. 2008;586:3751–57. [PMC free article] [PubMed]

142. Moser MB, Moser EI. Functional differentiation in the hippocampus. Hippocampus. 1998;6:608–19. [PubMed]

143. Moser MB, Trommald M, Andersen P. An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses. Proc. Natl. Acad. Sci. USA. 1994;91:12673–75. [PMC free article] [PubMed]

144. Nimchinsky EA, Sabatini BL, Svoboda K. Structure and function of dendritic spines. Annu. Rev. Physiol. 2002;64:313–53. [PubMed]

145. Nottebohm F. Why are some neurons replaced in adult brain? J. Neurosci. 2002;22:624–28. [PubMed]

146. O’Brien JA, Lummis SC. Diolistic labeling of neuronal cultures and intact tissue using a hand-held gene gun. Nat. Protoc. 2006;1:1517–21. [PMC free article] [PubMed]

147. Olariu A, Cleaver KM, Cameron HA. Decreased neurogenesis in aged rats results from loss of granule cell precursors without lengthening of the cell cycle. J. Comp. Neurol. 2007;501:659–67. [PubMed]

148. Olariu A, Cleaver KM, Shore LE, Brewer MD, Cameron HA. A natural form of learning can increase and decrease the survival of new neurons in the dentate gyrus. Hippocampus. 2005;15:750–62. [PubMed]

149. O’Malley A, O’Connell C, Murphy KJ, Regan CM. Transient spine density increases in the mid-molecular layer of hippocampal dentate gyrus accompany consolidation of a spatial learning task in the rodent. Neuroscience. 2000;99:229–32. [PubMed]

150. O’Malley A, O’Connell C, Regan CM. Ultrastructural analysis reveals avoidance conditioning to induce a transient increase in hippocampal dentate spine density in the 6 hour post-training period of consolidation. Neuroscience. 1998;87:607–13. [PubMed]

151. Oomen CA, Mayer JL, de Kloet ER, Joëls M, Lucassen PJ. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress. Eur. J. Neurosci. 2007;2612:3395–401. [PubMed]

152. Overstreet LS, Hentges ST, Bumaschny VF, de Souza FS, Smart JL, et al. A transgenic marker for newly born granule cells in dentate gyrus. J. Neurosci. 2004;24:3251–59. [PubMed]

153. Overstreet-Wadiche LS, Westbrook GL. Functional maturation of adult-generated granule cells. Hippocampus. 2006;16:208–15. [PubMed]

154. Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc. Natl. Acad. Sci. USA. 2007;104:5638–43. [PMC free article] [PubMed]

155. Perera TD, Coplan JD, Lisanby SH, Lipira CM, Arif M, et al. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J. Neurosci. 2007;27:4894–901. [PubMed]

156. Pham K, Nacher J, Hof PR, McEwen BS. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur. J. Neurosci. 2003;7:879–86. [PubMed]

157. Pokorný J, Yamamoto Postnatal ontogenesis of hippocampal CA1 area in rats. II. Development of ultrastructure in stratum lacunosum and moleculare. Brain Res. Bull. 1981;7:121–30. [PubMed]

158. Raber J, Rola R, LeFevour A, Morhardt D, Curley J, et al. Radiation induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat. Res. 2004;162:39–47. [PubMed]

159. Rahimi O, Claiborne BJ. Morphological development and maturation of granule neuron dendrites in the rat dentate gyrus. Prog. Brain Res. 2007;163:167–81. [PubMed]

160. Ramirez-Amaya V, Marrone DF, Gage FH, Worley PF, Barnes CA. Integration of new neurons into functional neural networks. J. Neurosci. 2006;26:12237–41. [PubMed]

161. Reif A, Fritzen S, Finger M, Strobel A, Lauer M, et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol. Psychiatry. 2006;11:514–22. [PubMed]

162. Revest JM, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol. Psychiatry. 2009 In press. [PubMed]

163. Ribak CE, Shapiro LA. Dendritic development of newly generated neurons in the adult brain. Brain. Res Rev. 2007;55:390–94. [PMC free article] [PubMed]

164. Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, et al. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp. Neurol. 2004;188:316–30. [PubMed]

165. Rolls ET, Kesner RP. A computational theory of hippocampal function, and empirical tests of the theory. Prog. Neurobiol. 2006;79:1–48. [PubMed]

166. Rusakov DA, Davies HA, Harrison E, Diana G, Richter-Levin G, et al. Ultrastructural synaptic correlates of spatial learning in rat hippocampus. Neuroscience. 1997;80:69–77. [PubMed]

167. Russo SJ, Mazei-Robison MS, Ables JL, Nestler EJ. Neurotrophic factors and structural plasticity in addiction. Neuropharmacology. 2009;56:73–82. [PMC free article] [PubMed]

168. Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat. Neurosci. 2007;10:1110–15. [PubMed]

169. Salic A, Mitchinson TJ. A chemical method for fast and sensitive detection of DNA synthesis in vivo. proc. Natl. Acad. Sci. USA. 2008;105:2415–20. [PMC free article] [PubMed]

170. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–9. [PubMed]

171. Sapolsky RM. Is impaired neurogenesis relevant to the affective symptoms of depression? Biol. Psychiatry. 2004;56:137–39. [PubMed]

172. Saxe MD, Battaglia F, Wang JW, Malleret G, David DJ, et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Natl. Acad. Sci. USA. 2006;103:17501–6. [PMC free article] [PubMed]

173. Saxe MD, Malleret G, Vronskaya S, Mendez I, Garcia AD, et al. Paradoxical influence of hippocampal neurogenesis on working memory. Proc. Natl. Acad. Sci. USA. 2007;104:4642–46. [PMC free article] [PubMed]

174. Schinder AF, Gage FH. A hypothesis about the role of adult neurogenesis in hippocampal function. Physiology (Bethesda) 2004;19:253–61. [PubMed]

175. Schlessinger AR, Cowan WM, Gottlieb DI. An autoradiographic study of the time of origin and the pattern of granule cell migration in the dentate gyrus of the rat. J. Comp. Neurol. 1975;159:149–75. [PubMed]

176. Schloesser RJ, Manji HK, Martinowich K. Suppression of adult neurogenesis leads to increased hypothalamo-pituitary-adrenal axis response. Neuroreport. 2009;20:553–57. [PMC free article] [PubMed]

177. Schmidt-Hieber C, Jonas P, Bischofberger J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature. 2004;429:184–87. [PubMed]

178. Schroeder T. Imaging stem-cell-driven regeneration in mammals. Nature. 2008;453:345–51. [PubMed]

179. Seress L. Comparative anatomy of the hippocampal dentate gyrus in adult and developing rodents, nonhuman primates and humans. Prog. Brain Res. 2007;163:23–41. [PubMed]

180. Seress L, Ribak CE. Postnatal development of CA3 pyramidal neurons and their afferents in the Ammon’s horn of rhesus monkeys. Hippocampus. 1995;5:217–31. [PubMed]

181. Seri B, García-Verdugo JM, McEwen BS, Alvarez-Buylla A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J. Neurosci. 2001;21:7153–60. [PubMed]

182. Selye H. The Stress of Life. McGraw-Hill; New York: 1976.

183. Shors TJ. From stem cells to grandmother cells: how neurogenesis relates to learning and memory. Cell Stem Cell. 2008;3:253–58. [PubMed]

184. Shors TJ, Chua C, Falduto J. Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus. J. Neurosci. 2001a;21:6292–97. [PubMed]

185. Shors TJ, Mathew J, Sisti HM, Edgecomb C, Beckoff S, Dalla C. Neurogenesis and helplessness are mediated by controllability in males but not in females. Biol. Psychiatry. 2007;62:487–95. [PMC free article] [PubMed]

186. Shors TJ, Miesagaes G, Beylin A, Zhao M, Rydel T, Gould E. Neurogenesis in the adult rat is involved in the formation of trace memories. Nature. 2001b;410:372–76. [PubMed]

187. Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus. 2002;12:578–84. [PMC free article] [PubMed]

188. Simon M, Czéh B, Fuchs E. Age-dependent susceptibility of adult hippocampal cell proliferation to chronic psychosocial stress. Brain Res. 2005;1049:244–48. [PubMed]

189. Snyder JS, Kee N, Wojtowicz JM. Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus. J. Neurophysiol. 2001;85:2423–31. [PubMed]

190. Snyder JS, Glover LR, Sanzone KM, Kamhi JF, Cameron HA. The effects of exercise and stress on the survival and maturation of adult-generated granule cells. Hippocampus. 2009a In press. [PMC free article] [PubMed]

191. Snyder JS, Hong NS, McDonald RJ, Wojtowicz JM. A role for adult neurogenesis in spatial long-term memory. Neuroscience. 2005;130:843–52. [PubMed]

192. Snyder JS, Radik R, Wojtowicz JM, Cameron HA. Anatomical gradients of adult neurogenesis and activity: Young neurons in the ventral dentate gyrus are activated by water maze training. Hippocampus. 2009b;19:360–70. [PMC free article] [PubMed]

193. Sousa N, Lukoyanov NV, Madeira MD, Almeida OF, Paula-Barbosa MM. Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement. Neuroscience. 2000;97:253–66. [PubMed]

194. Stewart MG, Davies HA, Sandi C, Kraev IV, Rogachevsky VV, et al. Stress suppresses and learning induces plasticity in CA3 of rat hippocampus: a three-dimensional ultrastructural study of thorny excrescences and their postsynaptic densities. Neuroscience. 2005;131:43–54. [PubMed]

195. Stranahan A, Kahlil D, Gould E. Social isolation delays the positive effects of running on adult neurogenesis. Nat. Neurosci. 2006;9:526–33. [PMC free article] [PubMed]

196. Stranahan A, Kahlil D, Gould E. Running induces widespread structural alterations in the hippocampus and entorhinal cortex. Hippocampus. 2007;17:1017–22. [PMC free article] [PubMed]

197. Surget A, Saxe M, Leman S, Ibarguen-Vargas Y, Chalon S, et al. Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol. Psychiatry. 2008;64:293–301. [PubMed]

198. Swann JW, Al-Noori S, Jiang M, Lee CL. Spine loss and other dendritic abnormalities in epilepsy. Hippocampus. 2000;10:617–25. [PubMed]

199. Swanson LW, Cowan WM. An autoradiographic study of the organization of the efferent connections of the hippocampal formation in the rat. J. Comp. Neurol. 1977;172:49–84. [PubMed]

200. Tanapat P, Galea LA, Gould L. Stress inhibits the proliferation of granule cell precursors in the developing dentate gyrus. Int. J. Dev. Neurosci. 1998;16:235–39. [PubMed]

201. Tanapat P, Hastings NB, Rydel TA, Galea LA, Gould E. Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J. Comp. Neurol. 2001;437:496–504. [PubMed]

202. Tashiro A, Makino H, Gage FH. Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J. Neurosci. 2007;27:3252–59. [PubMed]

203. Tashiro A, Zhao C, Gage FH. Retrovirus-mediated single-cell gene knockout technique in adult newborn neurons in vivo. Nat. Protoc. 2006;1:3049–55. [PubMed]

204. Thomas RM, Hotsenpiller G, Peterson DA. Acute psychosocial stress reduces cell survival in adult hippocampal neurogenesis without altering proliferation. J. Neurosci. 2007;27:2734–43. [PubMed]

205. Toni N, Laplagne DA, Zhao C, Lombardi G, Ribak CE, et al. Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat. Neurosci. 2008;11:901–7. [PMC free article] [PubMed]

206. Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, et al. Synapse formation on neurons born in the adult hippocampus. Nat. Neurosci. 2007;10:727–34. [PubMed]

207. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat. Rev. Neurosci. 2009;10:397–409. [PMC free article] [PubMed]

208. Van Der Borght K, Meerlo P, Luiten PG, Eggen BJ, Van Der Zee EA. Effects of active shock avoidance learning on hippocampal neurogenesis and plasma levels of corticosterone. Behav. Brain Res. 2005a;157:23–30. [PubMed]

209. Van Der Borght K, Wallinga AE, Luiten PG, Eggen BJ, Van Der Zee EA. Morris water maze learning in two rat strains increases the expression of the polysialylated form of the neural cell adhesion molecule in the dentate gyrus but has no effect on hippocampal neurogenesis. Behav. Neurosci. 2005b;119:926–32. [PubMed]

210. van Hooijdonk LW, Ichwan M, Dijkmans TF, Schouten TG, de Backer MW, et al. Lentivirus-mediated transgene delivery to the hippocampus reveals subfield specific differences in expression. BMC Neurosci. 2009;10:2. [PMC free article] [PubMed]

211. van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 1999;2:266–70. [PubMed]

212. van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. Nat. Rev. Neurosci. 2000;1:191–98. [PubMed]

213. van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature. 2002;415:1030–34. [PubMed]

214. van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 2005;25:8680–85. [PMC free article] [PubMed]

215. Veenema AH, de Kloet ER, de Wilde MC, Roelofs AJ, Kawata M, et al. Differential effects of stress on adult hippocampal cell proliferation in low and high aggressive mice. J. Neuroendocrinol. 2007;19:489–98. [PubMed]

216. Vega CJ, Peterson DA. Stem cell proliferative history in tissue revealed by temporal halogenated thymidine analog discrimination. Nat. Methods. 2005;2:167–69. [PubMed]

217. Vollmayr B, Simonis C, Weber S, Gass P, Henn F. Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness. Biol. Psychiatry. 2003;54:1035–40. [PubMed]

218. Waddell J, Shors TJ. Neurogenesis, learning and associative strength. Eur. J. Neurosci. 2008;27:3020–28. [PMC free article] [PubMed]

219. Walker TL, White A, Black DM, Wallace RH, Sah P, Bartlett PF. Latent stem and progenitor cells in the hippocampus are activated by neural excitation. J. Neurosci. 2008;28:5240–47. [PubMed]

220. Wang JW, David DJ, Monckton JE, Battaglia F, Hen R. Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J. Neurosci. 2008;28:1374–84. [PubMed]

221. Wang S, Scott BW, Wojtowicz JM. Heterogeneous properties of dentate granule neurons in the adult rat. J. Neurobiol. 2000;42:248–57. [PubMed]

222. Westenbroek C, Den Boer JA, Veenhuis M, Ter Horst GJ. Chronic stress and social housing differentially affect neurogenesis in male and female rats. Brain Res. Bull. 2004;64:303–8. [PubMed]

223. Winocur G, Wojtowicz JM, Sekeres M, Snyder JS, Wang S. Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus. 2006;16:296–304. [PubMed]

224. Wojtowicz JM, Kee N. BrdU assay for neurogenesis in rodents. Nat. Protoc. 2006;1:1399–405. [PubMed]

225. Woolley CS, Gould E, Frankfurt M, McEwen BS. Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J. Neurosci. 1990a;10:4035–39. [PubMed]

226. Woolley CS, Gould E, McEwen BS. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 1990b;531:225–31. [PubMed]

227. Xu HT, Pan F, Yang G, Gan WB. Choice of cranial window type for in vivo imaging affects dendritic spine turnover in the cortex. Nat. Neurosci. 2007;10:549–51. [PubMed]

228. Yamaguchi M, Saito H, Suzuki M, Mori K. Visualization of neurogenesis in the central nervous system using nestin promoter-GFP transgenic mice. Neuroreport. 2000;11:1991–96. [PubMed]

229. Zehr JL, Nichols LR, Schulz KM, Sisk CL. Adolescent development of neuron structure in dentate gyrus granule cells of male Syrian hamsters. Dev. Neurobiol. 2008;68:1517–26. [PMC free article] [PubMed]

230. Zhang CL, Zou Y, He W, Gage FH, Evans RM. A role for adult TLX-positive neural stem cells in learning and behavior. Nature. 2008;451:1004–7. [PubMed]

231. Zhao C, Teng EM, Summers RG, Jr, Ming GL, Gage FH. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J. Neurosci. 2006;26:3–11. [PubMed]