GABA neurons of the ventral periaqueductal gray area modulate behaviors associated with anxiety and conditioned fear.

Emotional behavioral responses related to anxiety and fear comprise the negative valence systems domain as defined by the Research Domain Criteria (RDoC) approach to categorizing related emotional behavioral constructs that are compromised in mental health disorders. Here, we evaluate the role of GABA neurons of the ventral periaqueductal gray (vPAG) in emotional behavioral responses related to anxiety and fear using a chemogenetic approach in Vgat-ires-Cre mice. Functional inhibition of vPAG GABA neurons using selective expression of inhibitory Gi-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADDs) enhanced anxiety-like behavior in the light-dark exploration and open-field tests. Functional inhibition of vPAG GABA neurons during the acquisition of conditioned fear impaired later performance of conditioned fear responses to the fear-associated context. No effects on spontaneous freezing behavior, fear generalization, or conditioned fear responses to the fear-associated cue were observed. Together, these data suggest that activity of vPAG GABA neurons underlies emotional behavioral responses related to anxiety and conditioned fear. As such, vPAG GABA neurons are a common neurophysiological correlate of the negative valence system and dysregulation of this population may contribute to the etiology of mental health disorders in which the negative valence systems domain is compromised.

Chronic stress dysregulates amygdalar output to the prefrontal cortex.

Chronic stress contributes to the neuropathology of mental health disorders, including those associated with anxiety. The basolateral amygdala (BLA) coordinates emotional behavioral responses through glutamatergic outputs to downstream regions such as the prefrontal cortex (PFC), nucleus accumbens core (NAcc) and bed nucleus of the stria terminalis (BNST). We explored the effects of chronic stress on BLA outputs to the PFC, NAcc and BNST using slice electrophysiology combined with optogenetics in two inbred mouse strains with distinct stress-induced anxiety responses. We found that ten consecutive days of chronic restraint stress enhanced pre-synaptic glutamate release at BLA-to-PFC synapses in C57BL/6J mice, but reduced pre-synaptic glutamate release at these synapses in DBA/2J mice. To assess the behavioral relevance of enhanced glutamate output at BLA-to-PFC synapses, we approximated the effects of chronic stress on the BLA-PFC circuit using optogenetics. We found that photostimulation of the BLA-PFC circuit in unstressed C57BL/6J mice produced persistent (i.e., post-stimulation) increased anxiety-like behavior and hyperactivity in the elevated plus-maze - a profile consistent with prototypical behavioral responses of stressed C57BL/6J mice. These data demonstrate that chronic stress dysregulates the BLA-PFC circuit by altering pre-synaptic glutamate release from BLA outputs, and provide a mechanism by which chronic stress can lead to increased anxiety.

The role of biogenic amine signaling in the bed nucleus of the stria terminals in alcohol abuse.

There is a growing body of evidence that suggests that stress and anxiety can influence the development of alcohol use disorders. This influence is believed to be due in part to persistent adaptations in discrete brain regions that underlie stress responsivity. One structure that has been proposed to be a site of important neuroadaptations underlying this behavior is the extended amygdala. The extended amygdala is a series of extensively inter-connected limbic structures including the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). These structures are critical regulators of behavioral and physiological activation associated with anxiety. Additionally, numerous reports have suggested that these regions are involved in increased drinking behavior associated with chronic alcohol exposure and withdrawal. The focus of this review will be to discuss the role of the BNST in regulation of behavior, to provide some insight in to the circuitry of the BNST, and to discuss the actions of the biogenic amines, serotonin, dopamine and norepinephrine, in the BNST.