Smaller hippocampal volume is reported in major depressive disorder (MDD). We hypothesize that it may be related to fewer granule neurons (GN) in the dentate gyrus (DG), a defect possibly reversible with antidepressants. We studied age-, sex-, and postmortem interval-matched groups: no major psychopathology (controls); unmedicated-MDD; and MDD treated with serotonin reuptake inhibitors (MDD*SSRI) or tricyclics (MDD*TCA). Frozen right hippocampi were fixed, sectioned (50 mm), immunostained with neuronal nuclear marker (NeuN), and counterstained with hematoxylin. GN and glial number, and DG and granule cell layer (GCL) volumes were stereologically estimated. Fewer GNs in the anterior DG were present in unmedicated-MDDs compared with controls (p ¼ 0.013). Younger age of MDD onset correlated with fewer GNs (p ¼ 0.021). Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs (p ¼ 0.028) and controls (p ¼ 0.032). Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicated-MDDs vs controls (p ¼ 0.008) and larger in MDD*SSRIs vs unmedicated-MDDs (po0.001), MDD*TCAs (po0.001), and controls (po0.001). Anterior GCL volume and GN number (r ¼ 0.594, p ¼ 0.001), and mid DG volume and GN number (r ¼ 0.398, p ¼ 0.044) were correlated. Anterior DG capillary density correlated with GN number (p ¼ 0.027), and with GCL (p ¼ 0.024) and DG (r ¼ 0.400, p ¼ 0.047) volumes. Posterior DG volume and GN number did not differ between groups. Fewer GNs in unmedicated-MDD without fewer neuronal progenitor cells, as previously reported, suggests a cell maturation or survival defect, perhaps related to MDD duration. This may contribute to a smaller hippocampus and is potentially reversed by SSRIs. Postmortem studies are correlative and animal studies are needed to test implied causal relationships.

Early life trauma is a risk factor for life-long disorders related to emotional processing, but knowledge underlying its enduring effect is incomplete. This study was motivated by the hypothesis that early life trauma increases amygdala-dependent threat responses via reduction in inhibition by parvalbumin (PV) interneurons and perineuronal nets (PNN) supporting PV cells, thus increasing excitability of the basolateral amygdala (BLA). From postnatal day (PN) 8-12, rat pups of both sexes were reared under normal bedding or under insufficient nest-building materials to induce maternal-to-infant maltreatment trauma (Scarcity-Adversity Model, SAM). At weaning age of PN23, the SAM group exhibited increased threat responses to predator odor. The SAM-induced increase in threat response was recapitulated in normally reared PN22-23 rats that were unilaterally depleted of PNN in the BLA by the enzymes, chondroitinase-ABC plus hyaluronidase at PN19-20. Light and electron microscopic analysis of the BLA revealed that anterior-to-mid levels of SAM group's BLAs exhibited decreased PNN intensity and decreased axo-somatic synapses between PV-to-principal pyramidal-like neurons and PV-to-PV. PV and PNN densities (cells/mm ) in the BLA of both control (CON) and SAM groups were still low at PN12 and SAM delayed the ontogenetic rise of PV intensity and PNN density. Moreover, PV cell density in the anterior-to-mid BLA correlated negatively with threat response of CON animals, but not for SAM animals. Thus, reduction of PNN-supported, PV-mediated somatic inhibition of pyramidal cells provides a mechanistic support for the enduring effect of early life maltreatment manifested as increasing innate threat response at weaning.

Modest antidepressant response rates of mood disorders (MD) encourage benzodiazepine (BZD) co-medication with debatable benefit. Adult hippocampal neurogenesis may underlie antidepressant responses, but diazepam co-administration impairs murine neuron maturation and survival in response to fluoxetine. We counted neural progenitor cells (NPCs), mitotic cells, and mature granule neurons postmortem in dentate gyrus (DG) from subjects with: untreated DSM-IV MD (n=17); antidepressant-treated MD (MD*ADT, n=10); benzodiazepine-antidepressant-treated MD (MD*ADT*BZD, n=7); no psychopathology or treatment (controls, n=18). MD*ADT*BZD had fewer granule neurons vs. MD*ADT in anterior DG and vs. controls in mid DG, and did not differ from untreated-MD in any DG subregion. MD*ADT had more granule neurons than untreated-MD in anterior and mid DG and comparable granule neuron number to controls in all dentate subregions. Untreated-MD had fewer granule neurons than controls in anterior and mid DG, and did not differ from any other group in posterior DG. MD*ADT*BZD had fewer NPCs vs. MD*ADT in mid DG. MD*ADT had more NPCs vs. untreated-MD and controls in anterior and mid DG. MD*ADT*BZD and MD*ADT had more mitotic cells in anterior DG vs. controls and untreated-MD. There were no between-group differences in mid DG in mitotic cells or in posterior DG for any cell type. Our results in mid-dentate, and to some degree anterior dentate, gyrus are consistent with murine findings that benzodiazepines counteract antidepressant-induced increases in neurogenesis by interfering with progenitor proliferation. We also confirmed, in this expanded sample, our previous finding of granule neuron deficit in untreated MD.

Food restriction (FR) evokes running, which may promote adaptive foraging in times of food scarcity, but can become lethal if energy expenditure exceeds caloric availability. Here, we demonstrate that chemogenetic activation of either the general medial prefrontal cortex (mPFC) pyramidal cell population, or the subpopulation projecting to dorsal striatum (DS) drives running specifically during hours preceding limited food availability, and not during ad libitum food availability. Conversely, suppression of mPFC pyramidal cells generally, or targeting mPFC-to-DS cells, reduced wheel running specifically during FR and not during ad libitum food access. Post mortem c-Fos analysis and electron microscopy of mPFC layer 5 revealed distinguishing characteristics of mPFC-to-DS cells, when compared to neighboring non–DS-projecting pyramidal cells: 1) greater recruitment of GABAergic activity and 2) less axo-somatic GABAergic innervation. Together, these attributes position the mPFC-to-DS subset of pyramidal cells to dominate mPFC excitatory outflow, particularly during FR, revealing a specific and causal role for mPFC-to-DS control of the decision to run during food scarcity. Individual differences in GABAergic activity correlate with running response to further support this interpretation. FR enhancement of PFC-to-DS activity may influence neural circuits both in studies using FR to motivate animal behavior and in human conditions hallmarked by FR.

No abstract

Young infant rat pups learn to approach cues associated with pain rather than learning amygdala-dependent fear. This approach response is considered caregiver-seeking and ecologically relevant within the context of attachment. With maturation, increases in the stress hormone corticosterone permit amygdala-dependent fear, which is crucial for survival during independent living. During the developmental transition from attachment to fear learning, maternal presence suppresses corticosterone elevation to block amygdala-dependent fear learning and re-engage the attachment circuitry. Early life trauma disrupts this developmental sequence by triggering a precocious increase of corticosterone, which permits amygdala-dependent threat responses. In this review, we explore the importance of the stress hormone corticosterone in infants’ transition from complete dependence on the caregiver to independence, with consideration for environmental influences on threat response ontogeny and mechanistic importance of social buffering of the stress response.

Anorexia nervosa is one of the most debilitating mental illnesses that emerges during adolescence, especially among females. Anorexia nervosa is characterized by severe voluntary food restriction and compulsive exercising, which combine to cause extreme body weight loss. We use activity-based anorexia (ABA), an animal model, to investigate the neurobiological bases of vulnerability to anorexia nervosa. This is a Mini-Review, focused on new ideas that have emerged based on recent findings from the Aoki Lab. Our findings point to the cellular and molecular underpinnings of three ABA phenomena: (1) age-dependence of ABA vulnerability; (2) individual differences in the persistence of ABA vulnerability during adolescence; (3) GABAergic synaptic plasticity in the hippocampus and the prefrontal cortex that contributes to the suppression of the maladaptive anorexia-like behaviors. We also include new data on the contribution to ABA vulnerability by cell type-specific knockdown of a GABA receptor subunit, α4, in dorsal hippocampus. Although the GABA system recurs as a key player in the gain of ABA resilience, the data predict why targeting the GABA system, singularly, may have only limited efficacy in treating anorexia nervosa. This is because boosting the GABAergic system may suppress the maladaptive behavior of over-exercising but could also suppress food consumption. We hypothesize that a sub-anesthetic dose of ketamine may be the magic bullet, since a single injection of this drug to mid-adolescent female mice undergoing ABA induction enhances food consumption and reduces wheel running, thereby reducing body weight loss through plasticity at excitatory synaptic inputs to both excitatory and inhibitory neurons. The same treatment is not as efficacious during late adolescence but multiple dosing of ketamine can suppress ABA vulnerability partially. This caveat underscores the importance of conducting behavioral, synaptic and molecular analyses across multiple time points spanning the developmental stage of adolescence and into adulthood. Since this is a Mini-Review, we recommend additional literature for readers seeking more comprehensive reviews on these subjects.

Food restriction (FR) evokes running, which may promote adaptive foraging in times of food scarcity, but can become lethal if energy expenditure exceeds caloric availability. Here, we demonstrate that chemogenetic activation of either the general medial prefrontal cortex (mPFC) pyramidal cell population, or the subpopulation projecting to dorsal striatum (DS) drives running specifically during hours preceding limited food availability, and not during ad libitum food availability. Conversely, suppression of mPFC pyramidal cells generally, or targeting mPFC-to-DS cells, reduced wheel running specifically during FR and not during ad libitum food access. Post-mortem c-Fos analysis and electron microscopy of mPFC layer 5 revealed distinguishing characteristics of mPFC-to-DS cells, when compared to neighboring non-DS projecting pyramidal cells: 1) greater recruitment of GABAergic activity and 2) less axo-somatic GABAergic innervation. Together, these attributes position the mPFC-to-DS subset of pyramidal cells to dominate mPFC excitatory outflow, particularly during FR, revealing a specific and causal role for mPFC-to-DS control of the decision to run during food scarcity. Individual differences in GABAergic activity correlate with running response to further support this interpretation. FR enhancement of PFC-to-DS activity may influence neural circuits both in studies using FR to motivate animal behavior and in human conditions hallmarked by FR.