Biology subjects

Evans-Strong, A.

Publications and source records attributed to Evans-Strong, A..

3 recordsLinked to original sources

bioRxiv2023

Experience-dependent information routing through the basolateral amygdala

The basolateral amygdala (BLA) is an emotional processing hub and is well-established to influence both positive and negative valence processing. Selective engagement of a heterogeneous cell population in the BLA is thought to contribute to this flexibility in valence processing. However, how this process is impacted by previous experiences which influence valence processing is unknown. Here we demonstrate that previous positive (EE) or negative (chronic unpredictable stress) experiences differentially influence the activity of specific populations of BLA principal neurons projecting to either the nucleus accumbens core or bed nucleus of the stria terminalis. Using chemogenetic manipulation of these projection-specific neurons we can mimic or occlude the effects of chronic unpredictable stress or enriched environment on valence processing to bidirectionally control avoidance behaviors and stress-induced helplessness. These data demonstrate that previous experiences influence the responsiveness of projection-specific BLA principal neurons, biasing information routing through the BLA, to govern valence processing.

neuroscience↗

bioRxiv2023

Witnessed trauma exposure induces fear in mice through a reduction in endogenous neurosteroid synthesis

Neurosteroids have been implicated in the pathophysiology of post-traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrate that both mice directly subjected to the threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5-reductase type 2, is decreased in the basolateral amygdala (BLA), which is a major emotional processing hub implicated in PTSD. We demonstrate that knockdown of 5-reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas treatment with an exogenous, synthetic neuroactive steroid GABAA receptor PAM with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound]) decreases the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5-reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma.

neuroscience↗

bioRxiv2022

Semaphorin 4D induced inhibitory synaptogenesis restores benzodiazepine sensitivity in a mouse model of Status Epilepticus

Previously we demonstrated that intra-hippocampal infusion of purified, Semaphorin 4D (Sema4D) extracellular domain into the mouse hippocampus rapidly promotes formation of GABAergic synapses and decreases seizure susceptibility in mice. Given the relatively fast action of Sema4D treatment revealed by these studies, we sought to determine the time course of Sema4D treatment on hippocampal network activity using an acute hippocampal slice preparation. We performed long-term extracellular recordings from area CA1 encompassing a 2 hour application of Sema4D and found that hippocampal excitation is suppressed hours following treatment. We also asked if Sema4D treatment could ameliorate seizures in an acute seizure model: the kainic acid (KA) mouse model of Status Epilepticus (SE). We demonstrate that Sema4D treatment suppresses seizures and lessens benzodiazepine (BZD) insensitivity which is a hallmark of refractory SE. Lastly, we sought to explore alternative methods of Sema4D delivery to hippocampus and thus created an Adeno Associated Virus expressing the extracellular domain of Sema4D. Our data reveal that virally delivered, chronically overexpressed Sema4D extracellular domain promotes GABAergic synapse formation and suppresses seizure activity similar to the actions of purified Sema4D protein. These results provide proof of concept that Sema4D-mediated GABAergic synapse development could combat BZD insensitivity in intractable forms of epilepsy, and that viral delivery of Sema4D is an efficacious and promising delivery method.

neuroscience↗