UCLA

Learning about context is essential for appropriate behavioral strategies, though pathologically strong contextual memories may form the basis for anxiety disorders such as PTSD. Though the general network of brain regions involved in this learning has been characterized, how neural representations in each region contribute to memory formation and recall, as well as how cholinergic signaling affects normal and maladaptive contextual learning, is not well understood. I used catFISH to compare short-term contextual fear memory reactivation across hippocampus (DH), basolateral amygdala (BLA), prelimbic and infralimbic cortices (mPFC). I found that while DH reactivation is related to contextual processing, BLA reactivation is related to recall of contextual fear memory; mPFC reactivation tracked both contextual and fear information (Ch2). To follow up, I used Fos-Cre mice to tag a contextual fear memory representation in BLA with the inhibitory proton pump ArchT. I then inactivated these memory neurons during a return to the original context, and found that it impaired recall, but that if the memory was first allowed to be recalled, ongoing fear behavior was not disrupted. This effect was similar at both recent and remote time points (Ch2). In order to probe how acetylcholine (ACh) in DH affects contextual processing, I used ChAT-Ai32 mice to selectively activate medial-septal cholinergic inputs to DH with ChR2 during contextual exposure. After pairing the context with shock, mice with enhanced ACh during contextual encoding showed higher levels of fear, suggesting stronger contextual memory formation. I also tested and confirmed the effects of light stimulation using anesthetized recording with choline biosensors (Ch3). As ACh increased the strength of contextual memories, I tested whether it was involved in maladaptive contextual fear in Stress-enhanced fear learning (SEFL), our rat model of sensitization in PTSD. I blocked muscarinic cholinergic signaling in DH or BLA using scopolamine before a traumatic event: 15 unsignaled shocks. I found that this blockade in either brain region not only disrupted fear to the trauma context, but blocked sensitization to a new context normally observed in the model. In DH, though sensitization to new contexts was blocked, sensitization to new tones was intact, suggesting a new role for ACh in DH in controlling contextual sensitization after trauma (Ch4).