Timothy J. Schoenfeld

Stress, stress hormones, and adult neurogenesis.

The dentate gyrus of the hippocampus continues to produce new neurons throughout adulthood. Adult neurogenesis has been linked to hippocampal function, including learning and memory, anxiety regulation and feedback of the stress response. It is thus not surprising that stress, which affects hippocampal function, also alters the production and survival of new neurons. Glucocorticoids, along with other neurochemicals, have been implicated in stress-induced impairment of adult neurogenesis. Paradoxically, increases in corticosterone levels are sometimes associated with enhanced adult neurogenesis in the dentate gyrus. In these circumstances, the factors that buffer against the suppressive influence of elevated glucocorticoids remain unknown; their discovery may provide clues to reversing pathological processes arising from chronic exposure to aversive stress.

Physical Exercise Prevents Stress-Induced Activation of Granule Neurons and Enhances Local Inhibitory Mechanisms in the Dentate Gyrus

Physical exercise is known to reduce anxiety. The ventral hippocampus has been linked to anxiety regulation but the effects of running on this subregion of the hippocampus have been incompletely explored. Here, we investigated the effects of cold water stress on the hippocampus of sedentary and runner mice and found that while stress increases expression of the protein products of the immediate early genes c-fos and arc in new and mature granule neurons in sedentary mice, it has no such effect in runners. We further showed that running enhances local inhibitory mechanisms in the hippocampus, including increases in stress-induced activation of hippocampal interneurons, expression of vesicular GABA transporter (vGAT), and extracellular GABA release during cold water swim stress. Finally, blocking GABAA receptors in the ventral hippocampus, but not the dorsal hippocampus, with the antagonist bicuculline, reverses the anxiolytic effect of running. Together, these results suggest that running improves anxiety regulation by engaging local inhibitory mechanisms in the ventral hippocampus.

Adult Neurogenesis and Mental Illness

Several lines of evidence suggest that adult neurogenesis, the production of new neurons in adulthood, may play a role in psychiatric disorders, including depression, anxiety, and schizophrenia. Medications and other treatments for mental disorders often promote the proliferation of new neurons; the time course for maturation and integration of new neurons in circuitry parallels the delayed efficacy of psychiatric therapies; adverse and beneficial experiences similarly affect development of mental illness and neurogenesis; and ablation of new neurons in adulthood alters the behavioral impact of drugs in animal models. At present, the links between adult neurogenesis and depression seem stronger than those suggesting a relationship between new neurons and anxiety or schizophrenia. Yet, even in the case of depression there is currently no direct evidence for a causative role. This article reviews the data relating adult neurogenesis to mental illness and discusses where research needs to head in the future.

Differential Effects of Stress and Glucocorticoids on Adult Neurogenesis

Stress is known to inhibit neuronal growth in the hippocampus. In addition to reducing the size and complexity of the dendritic tree, stress and elevated glucocorticoid levels are known to inhibit adult neurogenesis. Despite the negative effects of stress hormones on progenitor cell proliferation in the hippocampus, some experiences which produce robust increases in glucocorticoid levels actually promote neuronal growth. These experiences, including running, mating, enriched environment living, and intracranial self-stimulation, all share in common a strong hedonic component. Taken together, the findings suggest that rewarding experiences buffer progenitor cells in the dentate gyrus from the negative effects of elevated stress hormones. This chapter considers the evidence that stress and glucocorticoids inhibit neuronal growth along with the paradoxical findings of enhanced neuronal growth under rewarding conditions with a view toward understanding the underlying biological mechanisms.

Adult neurogenesis: optimizing hippocampal function to suit the environment

Numerous studies have attempted to determine the function of adult neurogenesis in the hippocampus using methods to deplete new neurons and examine changes in behaviors associated with this brain region. This approach has produced a set of findings that, although not entirely consistent, suggest new neurons are associated with improved learning and reduced anxiety. This paper attempts to synthesize some of these findings into a model that proposes adaptive significance to experience-dependent alterations in new neuron formation. We suggest that the modulation of adult neurogenesis, as well as of the microcircuitry associated with new neurons, by experience prepares the hippocampus to meet the specific demands of an environment that is predictably similar to one that existed previously. Reduced neurogenesis that occurs with persistent exposure to a high threat environment produces a hippocampus that is more likely to respond with behavior that maximizes the chance of survival. Conversely, enhanced neurogenesis that occurs with continual exposure to a rewarding environment leads to behavior that optimizes the chances of successful reproduction. The persistence of this form of plasticity throughout adulthood may provide the neural substrate for adaptive responding to both stable and dynamic environmental conditions.

Stress and loss of adult neurogenesis differentially reduce hippocampal volume

BACKGROUND Hippocampal volume loss is a hallmark of clinical depression. Chronic stress produces volume loss in the hippocampus in humans and atrophy of CA3 pyramidal cells and suppression of adult neurogenesis in rodents. METHODS To investigate the relationship between decreased adult neurogenesis and stress-induced changes in hippocampal structure and volume, we compared the effects of chronic unpredictable restraint stress and inhibition of neurogenesis in a rat pharmacogenetic model. RESULTS Chronic unpredictable restraint stress over 4 weeks decreased total hippocampal volume, reflecting loss of volume in all hippocampal subfields and in both dorsal and ventral hippocampus. In contrast, complete inhibition of adult neurogenesis for 4 weeks led to volume reduction only in the dentate gyrus. With prolonged inhibition of neurogenesis for 8 or 16 weeks, volume loss spread to the CA3 region, but not CA1. Combining stress and inhibition of adult neurogenesis did not have additive effects on the magnitude of volume loss but did produce a volume reduction throughout the hippocampus. One month of chronic unpredictable restraint stress and inhibition of adult neurogenesis led to atrophy of pyramidal cell apical dendrites in dorsal CA3 and to neuronal reorganization in ventral CA3. Stress also significantly affected granule cell dendrites. CONCLUSIONS The findings suggest that adult neurogenesis is required to maintain hippocampal volume but is not responsible for stress-induced volume loss.

Gap Junctions in the Ventral Hippocampal-Medial Prefrontal Pathway Are Involved in Anxiety Regulation

Anxiety disorders are highly prevalent but little is known about their underlying mechanisms. Gap junctions exist in brain regions important for anxiety regulation, such as the ventral hippocampus (vHIP) and mPFC, but their functions in these areas have not been investigated. Using pharmacological blockade of neuronal gap junctions combined with electrophysiological recordings, we found that gap junctions play a role in theta rhythm in the vHIP and mPFC of adult mice. Bilateral infusion of neuronal gap junction blockers into the vHIP decreased anxiety-like behavior on the elevated plus maze and open field. Similar anxiolytic effects were observed with unilateral infusion of these drugs into the vHIP combined with contralateral infusion into the mPFC. No change in anxious behavior was observed with gap junction blockade in the unilateral vHIP alone or in the bilateral dorsal HIP. Since physical exercise is known to reduce anxiety, we examined the effects of long-term running on the expression of the neuronal gap junction protein connexin-36 among inhibitory interneurons and found a reduction in the vHIP. Despite this change, we observed no alteration in theta frequency or power in long-term runners. Collectively, these findings suggest that neuronal gap junctions in the vHIP–mPFC pathway are important for theta rhythm and anxiety regulation under sedentary conditions but that additional mechanisms are likely involved in running-induced reduction in anxiety.

New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats

Abstract Virtually all antidepressant agents increase the birth of granule neurons in the adult dentate gyrus in rodents, providing a key basis for the neurogenesis hypothesis of antidepressant action. The novel antidepressant ketamine, however, shows antidepressant activity in humans within hours, far too rapid for a mechanism involving neuronal birth. Ketamine could potentially act more rapidly by enhancing maturation of new neurons born weeks earlier. To test this possibility, we assessed the effects of S-ketamine (S-(+)-ketamine hydrochloride) injection on maturation, as well as birth and survival, of new dentate gyrus granule neurons in rats, using the immediate-early gene zif268, proliferating cell nuclear antigen, and BrdU, respectively. We show that S-ketamine has rapid effects on new neurons, increasing the proportion of functionally mature young granule neurons within 2 h. A single injection of S-ketamine also increased cell proliferation and functional maturation, and decreased depressive-like behavior, for at least 4 weeks in rats treated with long-term corticosterone administration (a depression model) and controls. However, the behavioral effects of S-ketamine on neophagia were unaffected by elimination of adult neurogenesis. Together, these results indicate that ketamine has surprisingly rapid and long-lasting effects on the recruitment of young neurons into hippocampal networks, but that ketamine has antidepressant-like effects that are independent of adult neurogenesis.

Lasting Adaptations in Social Behavior Produced by Social Disruption and Inhibition of Adult Neurogenesis

Research on social instability has focused on its detrimental consequences, but most people are resilient and respond by invoking various coping strategies. To investigate cellular processes underlying such strategies, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Social disruption produced a preference for familiar over novel conspecifics, a change that did not involve global memory impairments or increased anxiety. Using the neuropeptide oxytocin as a tool to increase neurogenesis in the hippocampus of disrupted rats restored preference for novel conspecifics to predisruption levels. Conversely, reducing the number of new neurons by limited inhibition of adult neurogenesis in naive transgenic GFAP–thymidine kinase rats resulted in social behavior similar to disrupted rats. Together, these results provide novel mechanistic evidence that social disruption shapes behavior in a potentially adaptive way, possibly by reducing adult neurogenesis in the hippocampus. SIGNIFICANCE STATEMENT To investigate cellular processes underlying adaptation to social instability, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Unexpectedly, these changes were accompanied by changes in social strategies without evidence of impairments in cognition or anxiety regulation. Restoring adult neurogenesis in disrupted rats using oxytocin and conditionally suppressing the production of new neurons in socially naive GFAP–thymidine kinase rats showed that loss of 6-week-old neurons may be responsible for adaptive changes in social behavior.

Anxiolytic Actions of Exercise in Absence of New Neurons

Physical exercise reduces anxiety‐like behavior in adult mice. The specific mechanisms that mediate this anxiolytic effect are unclear, but adult neurogenesis in the dentate gyrus has been implicated because it is robustly increased by running and has been linked to anxiodepressive‐like behavior. We therefore tested the effects of long‐term wheel running on anxiety‐like behavior in GFAP‐TK (TK) mice, a transgenic strain with complete ablation of adult neurogenesis. Five weeks of running reduced anxiety‐like behavior equally in both TK mice and wild type (WT) control mice on two tests, elevated plus‐maze and novelty‐suppressed feeding. WT and TK mice also had similar patterns of c‐fos expression in the hippocampus following anxiety testing. Following testing on the elevated plus‐maze, running reduced c‐fos expression in the dorsal dentate gyrus and CA3 in both WT and TK mice. Following testing on novelty‐suppressed feeding, running reduced c‐fos expression throughout the dentate gyrus and CA3 in both WT and TK mice. Interestingly, following testing on a less anxiogenic version of novelty‐suppressed feeding, running reduced c‐fos expression only in the dorsal dentate gyrus in both WT and TK mice, supporting earlier suggestions that the dorsal hippocampus is less involved in emotional behavior than the ventral region. These results suggest that although running increases adult neurogenesis, new neurons are not involved in the decreased anxiety‐like behavior or hippocampal activation produced by running.