Active Avoidance Learning Requires Prefrontal Suppression of Amygdala-Mediated Defensive Reactions

Abstract

Signaled active avoidance (AA) paradigms train subjects to prevent an aversive outcome by performing a learned behavior during the presentation of a conditioned cue. This complex form of conditioning involves Pavlovian and instrumental components, which produce competing behavioral responses that must be reconciled for the subject to successfully avoid an aversive stimulus. In signaled AA paradigm for rat, we tested the hypothesis that the instrumental component of AA training recruits infralimbic prefrontal cortex (ilPFC) to inhibit central amygdala (CeA) mediated Pavlovian reactions. Pre-training lesions of ilPFC increased conditioned freezing while causing a corresponding decrease in avoidance; lesions of CeA produced opposite effects, reducing freezing and facilitating avoidance behavior. Pharmacological inactivation experiments demonstrated that ilPFC is relevant to both acquisition and expression phases of AA learning. Inactivation experiments also revealed that AA produces an ilPFC-mediated diminution of Pavlovian reactions that extends beyond the training context, even when the conditioned stimulus is presented in an environment that does not allow the avoidance response. Finally, injection of a protein synthesis inhibitor into either ilPFC or CeA impaired or facilitated AA, respectively, showing that avoidance training produces two opposing memory traces in these regions. These data support a model in which AA learning recruits ilPFC to inhibit CeA-mediated defense behaviors, leading to a robust suppression of freezing that generalizes across environments. Thus, ilPFC functions as an inhibitory interface, allowing instrumental control over an aversive outcome to attenuate the expression of freezing and other reactions to conditioned threat.

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

“…Given the observed behavioural effects of CSD, specific brain regions important in the circuitries of fear conditioning (AMYG, vHIPP (Maren et al, 2013)), avoid-escape learning (AMYG, mPFC (Moscarello and LeDoux, 2013)), specific learned helplessness (mPFC (Amat et al, 2005;Pryce et al, 2011)) and fatigue (DeLuca et al, 2009), were investigated in terms of CSD effects on transcriptome-level gene expression, with brains collected at day 17. Importantly, these same regions exhibit altered structure-function-molecular genetic changes in depression e.g.…”

“…Next generation sequencing and canonical pathway analysis were applied to conduct a hypothesis-free, transcriptome-level analysis of effects of CSD on gene expression in specific brain regions. The regions selected for study, ventral hippocampus, medial prefrontal cortex, and central and basolateral nuclei of amygdala, are fundamental to the neurocircuitries underlying the behaviours under study here (Amat et al, 2005;Maren et al, 2013;Moscarello and LeDoux, 2013) as well as the corresponding depression psychopathologies (Capuron et al, 2007;Disner et al, 2011;Mayberg, 2003;Price and Drevets, 2010;Savitz et al, 2013;Sibille et al, 2009;Strigo et al, 2008). 7…”

Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression

“…In mouse, the amygdala, mPFC and hippocampus constitute a major circuit in the regulation of aversive stimulus processing, whereby input from the mPFC onto GABA interneurons in the basolateral complex of the amygdala constitutes major top-down inhibition of fear responding, learning and memory (Herry et al, 2008). CPS mice exhibit increased Pavlovian fear learning and learned helplessness (Azzinnari et al, 2014;Fuertig et al, 2016), effects which are likely to be underlain by increased amygdala (re)activity, and in turn to be partly the result of reduced top-down inhibition (Lüthi and Lüscher, 2014;Moscarello and LeDoux, 2013). Therefore, it will be important to build on the present evidence for increased between-network FC involving the amygdala in CPS mice in terms of understanding the changes in the excitation-inhibition between these networks.…”

Modelos animales de miedo y ansiedad: descripciones neuro-conductuales

“…A esta prueba se le conoce como evitación "activa", porque el animal debe ejecutar una conducta para poder evitar el estímulo incondicionado (Choi, Cain & LeDoux, 2010). Esta conducta se espera que sea emitida en presencia del estímulo condicionado, casi siempre, un tono (Moscarello & LeDoux, 2013), pues este estímulo le genera "pistas" al animal para anticipar un peligro.…”

“…Además, ambos tipos de pruebas (el condicionamiento propiamente y la evitación activa), provocan dos tipos de conducta contrarias, ya que cuando el animal se condiciona al miedo, emite la conducta de "freezing", mientras que en la evitación activa el animal debe movilizarse para evitar el EI (Moscarello & LeDoux, 2013). Por supuesto, para que un animal evite un estímulo aversivo teniendo "pistas" de su anticipación (por ejemplo, el sonido), debe primero aprender las pistas específicas que predicen ese estímulo.…”