Dissecting the Functional Heterogeneity of Serotonergic Systems That Regulate Fear and Panic

Indiana University-Purdue University Indianapolis (IUPUI)Serotonin (5-HT) is heavily implicated in severe anxiety and trauma-related disor-ders, such as panic and post-traumatic stress disorders. Overall, site-specific pharmacolog-ical manipulations show that while 5-HT enhances anxiety-associated/avoidance behaviors in the amygdala, 5-HT inhibits panic-associated escape behaviors in the perifornical hypo-thalamus region (PeFR). Yet, our understanding of how specific serotonergic networks and co-transmitters regulate these conditions, but also other aspects of innate panic (e.g., car-dioexcitation or thermal response that occur during a flight or escape response) or condi-tioned fear behaviors is still elusive. Therefore, utilizing circuit-based gain- and loss-of-function approaches to selectively manipulate amygdala- and PeFR-projecting sero-tonergic systems, we hypothesize that specific serotonergic networks projecting to the amygdala and PeFR respectively enhance conditioned fear responses and attenuate innate panic-associated behaviors and physiological responses. There are two main chapters in this dissertation. In Chapter III, retrograde tracing revealed that the amygdala-projecting neurons from dorsal Raphe (DR) were almost exclusively serotonergic (92-95%) concen-trated in the dorsal/ventral (DRD/DRV) DR, with few non-serotonergic neurons. While selective lesioning of this network with saporin toxin (SAP) facilitated the extinction of conditioned fear behavior, selective optogenetic activation of amygdala-projecting DRD/DRV cell bodies using intersectional genetics reduced extinction of conditioned fear behavior and enhanced anxiety avoidance. In Chapter IV, retrograde tracing showed that the PeFR was innervated by equally selective serotonergic networks concentrated in the lateral wings DR (lwDR) and median Raphe (MR). Contrasting with the results from the amygdala-innervating 5-HT system, lesioning the PeFR-projecting serotonergic network from lwDR/MR was accompanied by reduced extinction of conditioned fear behavior, in-creased anxiety avoidance, and increased CO2-induced panic (elevated escape responses and enhanced cardioexcitation). Conversely, selective activation of lwDR/MR serotonergic terminals in the PeFR decreased anxiety-associated behaviors; inhibited CO2-induced panic, and induced unconditioned and conditioned place preferences. The circuit-based ap-proach data presented here show that amygdala- and PeFR-projecting 5-HT neurons com-prise distinct circuits underlying opposite roles enhancing anxiety/fear responses in the amygdala and dampening fear/panic responses in the PeFR. The identification of distinct circuits controlling anxiety, fear, and panic responses is a fundamental step towards the development of more effective therapies for psychiatric conditions such as anxiety and trauma-related disorders.2021-11-0

Translational approach to studying panic disorder in rats: Hits and misses

Luiz Carlos Schenberg, Fagna Giacomin Schimitel, Rubia de Souza Armini, Cristian Setubal Bernabe, Caroline Azevedo Rosa, Sergio Tufik, Claudia Janaina Torres Muller, Jeyce Willig Quintino-dos-Santos. Translational Approach to Studying Panic Disorder in Rats: Hits and Misses. Neurosci. Biobehav. Rev. XX (X) XXX-XXX, 2014. Panic disorder (PD) patients are specifically sensitive to 5-7% carbon dioxide. Another startling feature of clinical panic is the counterintuitive lack of increments in 'stress hormones'. PD is also more frequent in women and highly comorbid with childhood separation anxiety (CSA). On the other hand, increasing evidence suggests that panic is mediated at dorsal periaqueductal grey matter (DPAG). in line with prior studies showing that DPAG-evoked panic-like behaviours are attenuated by clinically-effective treatments with panicolytics, we show here that (i) the DPAG harbors a hypoxia-sensitive alarm system, which is activated by hypoxia and potentiated by hypercapnia, (ii) the DPAG suffocation alarm system is inhibited by clinically-effective treatments with panicolytics, (iii) DPAG stimulations do not increase stress hormones in the absence of physical exertion, (iv) DPAG-evoked panic-like behaviours are facilitated in neonatally-isolated adult rats, a model of CSA, and (v) DPAG-evoked responses are enhanced in the late diestrus of female rats. Data are consistent with the DPAG mediation of both respiratory and non-respiratory types of panic attacks. (C) 2014 Elsevier B.V. All rights reserved.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)UFES/AFIPUniv Fed Espirito Santo, Dept Physiol Sci, Vitoria, ES, BrazilUniv Fed Espirito Santo, Dept Sports, Vitoria, ES, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilCNPq: 55203345/11UFES/AFIP: 23068020409/2010-43Web of Scienc