Circuit and synaptic mechanisms of repeated stress: Perspectives from differing contexts, duration, and development

Abstract

The current review is meant to synthesize research presented as part of a symposium at the 2016 Neurobiology of Stress workshop in Irvine California. The focus of the symposium was "Stress and the Synapse: New Concepts and Methods" and featured the work of several junior investigators. The presentations focused on the impact of various forms of stress (altered maternal care, binge alcohol drinking, chronic social defeat, and chronic unpredictable stress) on synaptic function, neurodevelopment, and behavioral outcomes. One of the goals of the symposium was to highlight the mechanisms accounting for how the nervous system responds to stress and their impact on outcome measures with converging effects on the development of pathological behavior. Dr. Kevin Bath's presentation focused on the impact of disruptions in early maternal care and its impact on the timing of hippocampus maturation in mice, finding that this form of stress drove accelerated synaptic and behavioral maturation, and contributed to the later emergence of risk for cognitive and emotional disturbance. Dr. Scott Russo highlighted the impact of chronic social defeat stress in adolescent mice on the development and plasticity of reward circuity, with a focus on glutamatergic development in the nucleus accumbens and mesolimbic dopamine system, and the implications of these changes for disruptions in social and hedonic response, key processes disturbed in depressive pathology. Dr. Kristen Pleil described synaptic changes in the bed nuclei of the stria terminalis that underlie the behavioral consequences of allostatic load produced by repeated cycles of alcohol binge drinking and withdrawal. Dr. Eric Wohleb and Dr. Ron Duman provided new data associating decreased mammalian target of rapamycin (mTOR) signaling and neurobiological changes in the synapses in response to chronic unpredictable stress, and highlighted the potential for the novel antidepressant ketamine to rescue synaptic and behavioral effects. In aggregate, these presentations showcased how divergent perspectives provide new insights into the ways in which stress impacts circuit development and function, with implications for understanding emergence of affective pathology.

Keywords: Bed nuclei of the stria terminalis; Corticotropin-releasing factor; Early-life stress; Hippocampus; Major depressive disorder; Mammalian target of rapamycin; Neuropeptide Y; Nucleus accumbens; Prefrtonal cortex; Resilience; Susceptibility.

Fig. 1

Impact of ELS on growth and maturation of the murine hippocampus. (A) Across early postnatal development there is a significant decline in rates of cell proliferation and differentiation. (B) Across this same period there is a gradual increase in makers of cellular and circuit maturation including myelination, synaptic differentiation, and interneuron integration. Across these measures, we find that ELS (dashed) leads to a more rapid silencing of neurogenesis and an earlier onset and completion of maturational processes in the hippocampus of the mouse.

Fig. 2

mTORC1-p70S6 kinase signaling in synaptic plasticity effects of stress and rapid antidepressant actions. In rodents exposed to stress and patients with MDD, REDD1 expression is increased leading to reduced mTORC1-p70S6 kinase signaling and decreased synapse number and function. Viral-mediated overexpression of REDD1 or dominant negative forms of p70S6 kinase cause similar neuronal and behavioral effects. In contrast, treatment with ketamine or scopolamine causes glutamate influx in the PFC promoting AMPA receptor activation, which increased mTORC1-p70S6K signaling, contributing to increased synaptic plasticity underlying antidepressant responses. Similar antidepressant responses can be attained with viral-mediated expression of constitutively active forms of p70S6 kinase.

Fig. 3

GABA interneurons in the medial PFC mediate antidepressant effects of ketamine and scopolamine. GABA interneurons in the medial PFC tonically inhibit excitatory pyramidal neurons (Δ). Rapid antidepressant drugs antagonize GABA interneurons (somatostatin (SST); parvalbumin (PV)), leading to disinhibition of pyramidal neurons and subsequent stimulation of neuronal activity-dependent molecular pathways in pyramidal neurons that underlie behavioral responses to ketamine and scopolamine.