Synaptic Organization-Function Relationships of Amygdala Interneurons Supporting Associative Learning.

Coordinated activity of basolateral amygdala (BLA) GABAergic interneurons (INs) and glutamatergic principal cells (PCs) is critical for associative learning, however the microcircuit organization-function relationships of distinct IN classes remain uncertain. Here, we show somatostatin (SOM) INs provide inhibition onto, and are excited by, local PCs, whereas vasoactive intestinal peptide (VIP) INs are driven by extrinsic afferents. Parvalbumin (PV) INs inhibit PCs and are activated by local and extrinsic inputs. Thus, SOM and VIP INs exhibit complementary roles in feedback and feedforward inhibition, respectively, while PV INs contribute to both microcircuit motifs. Functionally, each IN subtype reveals unique activity patterns across fear- and extinction learning with SOM and VIP INs showing most divergent characteristics, and PV INs display an intermediate phenotype parallelling synaptic data. Finally, SOM and PV INs dynamically track behavioral state transitions across learning. These data provide insight into the synaptic microcircuit organization-function relationships of distinct BLA IN classes.

Prefrontal cortical dynorphin peptidergic transmission constrains threat-driven behavioral and network states.

Prefrontal cortical (PFC) circuits provide top-down control of threat reactivity. This includes ventromedial PFC (vmPFC) circuitry, which plays a role in suppressing fear-related behavioral states. Dynorphin (Dyn) has been implicated in mediating negative affect and maladaptive behaviors induced by severe threats and is expressed in limbic circuits, including the vmPFC. However, there is a critical knowledge gap in our understanding of how vmPFC Dyn-expressing neurons and Dyn transmission detect threats and regulate expression of defensive behaviors. Here, we demonstrate that Dyn cells are broadly activated by threats and release Dyn locally in the vmPFC to limit passive defensive behaviors. We further demonstrate that vmPFC Dyn-mediated signaling promotes a switch of vmPFC networks to a fear-related state. In conclusion, we reveal a previously unknown role of vmPFC Dyn neurons and Dyn neuropeptidergic transmission in suppressing defensive behaviors in response to threats via state-driven changes in vmPFC networks.

Prefrontal cortical dynorphin peptidergic transmission constrains threat-driven behavioral and network states.

Prefrontal cortical (PFC) circuits provide top-down control of threat reactivity. This includes ventromedial PFC (vmPFC) circuitry, which plays a role in suppressing fear-related behavioral states. Dynorphin (Dyn) has been implicated in mediating negative affect and mal-adaptive behaviors induced by severe threats and is expressed in limbic circuits, including the vmPFC. However, there is a critical knowledge gap in our understanding of how vmPFC Dyn-expressing neurons and Dyn transmission detect threats and regulate expression of defensive behaviors. Here, we demonstrate that Dyn cells are broadly activated by threats and release Dyn locally in the vmPFC to limit passive defensive behaviors. We further demonstrate that vmPFC Dyn-mediated signaling promotes a switch of vmPFC networks to a fear-related state. In conclusion, we reveal a previously unknown role of vmPFC Dyn neurons and Dyn neuropeptidergic transmission in suppressing defensive behaviors in response to threats via state-driven changes in vmPFC networks.

Endocannabinoid release at ventral hippocampal-amygdala synapses regulates stress-induced behavioral adaptation.

The endocannabinoid (eCB) system is a key modulator of glutamate release within limbic neurocircuitry and thus heavily modulates stress responsivity and adaptation. The ventral hippocampus (vHPC)-basolateral amygdala (BLA) circuit has been implicated in the expression of negative affective states following stress exposure and is modulated by retrograde eCB signaling. However, the mechanisms governing eCB release and the causal relationship between vHPC-BLA eCB signaling and stress-induced behavioral adaptations are not known. Here, we utilized in vivo optogenetic- and biosensor-based approaches to determine the temporal dynamics of activity-dependent and stress-induced eCB release at vHPC-BLA synapses. Furthermore, we demonstrate that genetic deletion of cannabinoid type-1 receptors selectively at vHPC-BLA synapses decreases active stress coping and exacerbates stress-induced avoidance and anhedonia phenotypes. These data establish the in vivo determinants of eCB release at limbic synapses and demonstrate that eCB signaling within vHPC-BLA circuitry serves to counteract adverse behavioral consequences of stress.

Synaptic and cellular endocannabinoid signaling mechanisms regulate stress-induced plasticity of nucleus accumbens somatostatin neurons.

Interneuron populations within the nucleus accumbens (NAc) orchestrate excitatory-inhibitory balance, undergo experience-dependent plasticity, and gate-motivated behavior, all biobehavioral processes heavily modulated by endogenous cannabinoid (eCB) signaling. While eCBs are well known to regulate synaptic plasticity onto NAc medium spiny neurons and modulate NAc function at the behavioral level, how eCBs regulate NAc interneuron function is less well understood. Here, we show that eCB signaling differentially regulates glutamatergic and feedforward GABAergic transmission onto NAc somatostatin-expressing interneurons (NAcSOM+) in an input-specific manner, while simultaneously increasing postsynaptic excitability of NAcSOM+ neurons, ultimately biasing toward vHPC (ventral hippocampal), and away from BLA (basolateral amygdalalar), activation of NAcSOM+ neurons. We further demonstrate that NAcSOM+ are activated by stress in vivo and undergo stress-dependent plasticity, evident as a global increase in intrinsic excitability and an increase in excitation-inhibition balance specifically at vHPC, but not BLA, inputs onto NAcSOM+ neurons. Importantly, both forms of stress-induced plasticity are dependent on eCB signaling at cannabinoid type 1 receptors. These findings reveal eCB-dependent mechanisms that sculpt afferent input and excitability of NAcSOM+ neurons and demonstrate a key role for eCB signaling in stress-induced plasticity of NAcSOM+-associated circuits.

Opposing retrograde and astrocyte-dependent endocannabinoid signaling mechanisms regulate lateral habenula synaptic transmission.

The lateral habenula (LHb) encodes aversive states, and its dysregulation is implicated in neuropsychiatric disorders, including depression. The endocannabinoid (eCB) system is a neuromodulatory signaling system that broadly serves to counteract the adverse effects of stress; however, CB1 receptor signaling within the LHb can paradoxically promote anxiogenic- and depressive-like effects. Current reports of synaptic actions of eCBs in the LHb are conflicting and lack systematic investigation of eCB regulation of excitatory and inhibitory transmission. Here, we report that eCBs differentially regulate glutamatergic and GABAergic transmission in the LHb, exhibiting canonical and circuit-specific inhibition of both systems and an opposing potentiation of synaptic glutamate release mediated via activation of CB1 receptors on astrocytes. Moreover, simultaneous depression of GABA and potentiation of glutamate release increases the net excitation-inhibition ratio onto LHb neurons, suggesting a potential cellular mechanism by which cannabinoids may promote LHb activity and subsequent anxious- and depressive-like aversive states.

Corpus callosum size and homotopic connectivity in Autism spectrum disorder.

By examining how morphology of the corpus callosum (CC) in autism spectrum disorder (ASD) may affect functional communication across hemispheres, we hope to provide new insights into the structure-function relationship in the brain. We used a sample of 94 participants from the Autism Brain Imaging Data Exchange (ABIDE) database (55 typically-developing (TD) and 39 with ASD). The CC was segmented into five sub-regions (anterior, mid-anterior, central, mid-posterior, posterior) using FreeSurfer software, which were further examined for group differences. The total volume and specific sub-region volumes of the CC, and interhemispheric (homotopic) functional connectivity were calculated, along with the relationship between volume and connectivity. These measures were correlated with social ability assessed by the Social Responsiveness Scale (SRS). The central sub-region of CC was significantly smaller in ASD, although there was no group difference in total CC volume. ASD participants also showed stronger homotopic connectivity in the superior frontal gyrus. SRS scores were negatively correlated with the CC central sub-region volumes in ASD. The findings of this study add to the body of research showing morphological differences in the CC in ASD as well as connectivity differences. The absence of a significant relationship between structure and homotopic functional connectivity aligns with previous findings.