Effects of electroconvulsive shock on the function, circuitry, and transcriptome of dentate gyrus granule neurons.

Therapeutic use of electroconvulsive shock (ECS) is 75% effective for the remission of treatment-resistant depression. Like other more common forms of antidepressant treatment such as fluoxetine, ECS has been shown to increase neurogenesis in the hippocampal dentate gyrus of rodent models. Yet the question of how ECS-induced neurogenesis supports improvement of depressive symptoms remains unknown. Here, we show that ECS-induced neurogenesis is necessary to improve depressive-like behavior of mice exposed to chronic corticosterone (Cort). We then use slice electrophysiology to show that optogenetic stimulation of adult-born neurons produces a greater hyperpolarization in mature granule neurons after ECS vs Sham treatment. We identify that this hyperpolarization requires the activation of metabotropic glutamate receptor 2 (mGluR2). Consistent with this finding, we observe reduced expression of the immediate early gene cFos in the granule cell layer of ECS vs Sham subjects. We then show that mGluR2 knockdown specifically in ventral granule neurons blunts the antidepressant-like behavioral effects of ECS. Using single nucleus RNA sequencing, we reveal major transcriptomic shifts in granule neurons after treatment with ECS+Cort or fluoxetine+Cort vs Cort alone. We identify a population of immature cells which has greater representation in both ECS+Cort and fluoxetine+Cort treated samples vs Cort alone. We also find global differences in ECS-vs fluoxetine-induced transcriptomic shifts. Together, these findings highlight a critical role for immature granule cells and mGluR2 signaling in the antidepressant action of ECS.

Pathway-specific GABAergic inhibition contributes to the gain of resilience against anorexia-like behavior of adolescent female mice.

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 Engages Prefrontal Corticostriatal Cells and Local Microcircuitry to Drive the Decision to Run versus Conserve Energy.

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.

Early life trauma increases threat response of peri-weaning rats, reduction of axo-somatic synapses formed by parvalbumin cells and perineuronal net in the basolateral nucleus of amygdala.

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/mm2 ) 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.

Benzodiazepines and the potential trophic effect of antidepressants on dentate gyrus cells in mood disorders.

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 post-mortem in dentate gyrus (DG) from subjects with: untreated Diagnostic and Statistical Manual of Mental Disorders (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.

Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression.

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 µm), 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=0.013). Younger age of MDD onset correlated with fewer GNs (p=0.021). Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs (p=0.028) and controls (p=0.032). Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicated-MDDs vs controls (p=0.008) and larger in MDD*SSRIs vs unmedicated-MDDs (p<0.001), MDD*TCAs (p<0.001), and controls (p<0.001). Anterior GCL volume and GN number (r=0.594, p=0.001), and mid DG volume and GN number (r=0.398, p=0.044) were correlated. Anterior DG capillary density correlated with GN number (p=0.027), and with GCL (p=0.024) and DG (r=0.400, p=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.