Brain-wide screen of prelimbic cortex inputs reveals a functional shift during early fear memory consolidation

Abstract

Memory formation and storage rely on multiple interconnected brain areas, the contribution of which varies during memory consolidation. The medial prefrontal cortex, in particular the prelimbic cortex (PL), was traditionally found to be involved in remote memory storage, but recent evidence points toward its implication in early consolidation as well. Nevertheless, the inputs to the PL governing these dynamics remain unknown. Here, we first performed a brain-wide, rabies-based retrograde tracing screen of PL engram cells activated during contextual fear memory formation in male mice to identify relevant PL input regions. Next, we assessed the specific activity pattern of these inputs across different phases of memory consolidation, from fear memory encoding to recent and remote memory recall. Using projection-specific chemogenetic inhibition, we then tested their functional role in memory consolidation, which revealed a hitherto unknown contribution of claustrum to PL inputs at encoding, and of insular cortex to PL inputs at recent memory recall. Both of these inputs further impacted how PL engram cells were reactivated at memory recall, testifying to their relevance for establishing a memory trace in the PL. Collectively, these data identify a spatiotemporal shift in PL inputs important for early memory consolidation, and thereby help to refine the working model of memory formation.

Network-Level Changes in the Brain Underlie Fear Memory Strength

“…Adding to the known involvement of the RSC [55,56] and the Re [57][58][59] in modulating fear memory formation and expression, our results revealed neural activity in these structures was increased during mild memory recall, but not during strong memory recall, when compared to unshocked controls. Although the hippocampus [48,49,[60][61][62], prelimbic [63][64][65], and cingulate cortex [66][67][68] are critical to contextual fear memory-related processes, we found no differences in their activation between groups, suggesting that the role of these structures in modulating the expression of fear of different intensities may not reflect in changes in overall activation levels.…”

State dependent constraints on claustrocortical communication and function

“…The claustrum provides a diffuse excitatory connection to almost all cortical regions [1][2][3][4][5] . The function of the claustrum has remained somewhat enigmatic as it has been implicated in cortical synchrony, sleep, stress, memory, attention, and decision making [6][7][8][9][10][11] . One challenge has been relating neural activity in the claustrum to these distinct processes, as the real-time measurement of identified claustrum neurons has only been reported in a select few instances 6,7,[11][12][13][14][15][16] .…”

“…in synchronized cortical states. However, the claustrum is also proposed to function in REM sleep and states of high attentional demand such as memory encoding or decision making 8,10,11,37,38 , suggesting activation during cortical desynchronization. This work raises the question of whether there is an optimal brain or behavioral state for claustrum communication with downstream targets in the mammalian brain.…”

A “double-edged” role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs

“…Interestingly, blockade of mGlu5 in thalamus also inhibited pain behaviors ( Fig. 2 ), possibly through projections to cortical regions such as somatosensory and insular cortices, with the latter projecting strongly to the prelimbic cortex ( 46 ). Previous studies showed increased mGlu5 receptor expression in the mPFC ipsilateral, but not contralateral, to peripheral nerve injury ( 45 ).…”