Selective contribution of brain microcircuits to the control of fear memories

Fear memory circuits are essential for normal response to threats but also underlie pathologies of excess fear such as post-traumatic stress disorder. Here we uncovered the contribution of a specific microcircuit to the formation of fear memories, bringing us one step closer to understanding the physiological basis of fear regulation.

HFSP Long-Term Fellow Maithe Arruda-Carvalho and colleagues
authored on Mon, 26 January 2015

Aversive memories are extraordinarily robust and long lasting, often leading to fear and anxiety disorders which prove resistant to treatment. A common model used to study such disorders is Pavlovian fear conditioning, a technique in which animals learn to associate the sound of a tone with a stressful footshock. Memory of that association is later assessed by exposing the animals to the tone in the absence of footshock, leading to the expression of a fear response in these animals. Two brain regions, medial prefrontal cortex (mPFC) and amygdala, are linked to fear and anxiety disorders and have been extensively shown to regulate the control of fear expression following Pavlovian fear conditioning. Two prefrontal cortex subregions in particular, prelimbic cortex (PL) and infralimbic cortex (IL), exert opposing roles in this regulation, with PL and IL respectively supporting and inhibiting fear responses. Given that both PL and IL exert these divergent roles over the same amygdalar neurons, it remains unclear how the integration of their inputs instructs fear responses. The current models stipulate that these regions achieve this dichotomy in behavioral output by recruiting different levels of excitation and inhibition in amygdala, with IL mostly recruiting inhibitory networks that enable fear inhibition. Only recently, however, the field achieved the technical tools to assess this.

Figure: Selective targeting of PFC-Amygdala microcircuits. Visualization of viral injection onto IL (A) and PL (B) and their axonal projections reaching amygdala (C-F) [from IL (C,E) and PL (D,F)]. Using this technique we can selectively target these microcircuits to dissect their contributions to the formation of fear memories. IL-infralimbic cortex, PL=prelimbic cortex, BA=basal amygdala, LA=lateral amygdala.

Our paper in the Journal of Neuroscience describes how we used optogenetics and ex vivo electrophysiology to functionally dissect the influence of prelimbic and infralimbic cortices on synaptic plasticity in amygdala following fear conditioning in mice. We saw that even though PL and IL recruited equivalent levels of excitation and inhibition in naïve animals, fear conditioning led to the selective strengthening of prelimbic inputs onto amygdala.  This fear-induced potentiation of prelimbic inputs was mediated by an increase in excitatory transmission without interfering with feedforward inhibition. These data provide a synaptic basis for the contribution of the mPFC-amygdala circuit to the encoding of fear memories and critically disambiguates the roles of prefrontal cortex subregions in the control of fear memory formation. Understanding how selective brain microcircuits regulate fear expression will be critical for uncovering the neurophysiological basis of disorders of excess fear such as post-traumatic stress disorder (PTSD).

Reference

Pathway-selective adjustment of prefrontal-amygdala transmission during fear encoding. Arruda-Carvalho M, Clem RL.  J Neurosci. 2014 Nov 19;34(47):15601-9. doi: 10.1523/JNEUROSCI.2664-14.2014.

Pubmed link