Distinct Neuronal Populations Contribute to Trace Conditioning and Extinction Learning in the Hippocampal CA1

Abstract

12Trace conditioning and extinction learning depend on the hippocampus, but it remains 13 unclear how ongoing neural activities in the hippocampus are modulated during different 14 learning processes. To explore this question, we performed calcium imaging in a large 15 number of individual CA1 neurons during both trace eye-blink conditioning and 16 subsequent extinction learning in mice. Using trial-averaged calcium fluorescence 17 analysis, we found direct evidence that in real time, as learning emerges, distinct 18 populations of CA1 cells contribute to trace conditioned learning versus extinction 19 learning. Furthermore, we examined network connectivity by calculating co-activity 20 between CA1 neuron pairs, and found that CA1 network connectivity is different between 21 conditioning and extinction and between correct versus incorrect behavioral responses 22 during trace conditioned learning. However, the overall connectivity density remains 23 constant across these behavioral conditions. Together, our results demonstrate that 24 distinct populations of CA1 neurons, forming different sub-networks with unique 25 connectivity patterns, encode different aspects of learning. 26 2 epilepsy, resulted in severe memory loss and an inability to form new declarative or 30 episodic memories 1,2 . Hippocampal atrophy is also associated with diseases related to 31 memory loss and cognitive decline including dementia and Alzheimer's disease [3][4][5][6][7] . Many 32 mechanistic studies have highlighted the importance of the hippocampus for spatial, 33 contextual, and associative learning in a variety of animal models 8,9 . 34 Various experimental paradigms have been devised to probe hippocampal-35 dependent forms of learning and memory. One such well-established paradigm is trace 36 eye blink conditioning, which requires an intact hippocampus 10-12 . In this experimental 37 design, subjects are presented with a conditioned stimulus (CS), such as a tone or light, 38 which reliably predicts an unconditioned stimulus (US), such as a puff of air or electrical 39 shock delivered to the subject's eyelid. In trace conditioning, the CS and US are separated 40 temporally by a quiescent trace interval. Over time, subjects will learn to associate the CS 41 with the US, generating a behavioral conditioned response to the CS 13-18 . Trace 42 conditioning acquisition depends on signaling at both nicotinic and muscarinic 43 acetylcholine receptors (AChRs) 19-26 and is mediated through NMDA receptor-dependent 44 plasticity 27 . 45The hippocampus is also required for context-dependent extinction learning 11 . 46Extinction learning is traditionally considered new learning that overrides a previously 47 learned relationship. In the example of trace conditioning, the subject learns that the 48 previously established CS is no longer predictive of a subsequent US. Extinction learning 49 after trace conditioning can be tested by the presentation of the CS without the associated 50 US, and monitoring the strength or presence of a conditio...

Visual association cortex links cues with conjunctions of reward and locomotor contexts

“…This balance was driven in part by gradual recruitment of subsets of neurons that responded to a cue as it became unrewarded, in addition to recruitment of other neurons driven by a newly rewarded cue. Neurons driven selectively by a cue in contexts where the cue has become both familiar and non-salient may constitute a kind of extinction trace, as observed in other brain areas (Mount et al, 2021;Reinert et al, 2021). Also surprising was the substantial set of excitatory POR neurons that responded to cues only when the mouse was stationary, in contrast to the strong bias in responses during locomotion observed in V1 (Andermann et al, 2011;Erisken et al, 2014;Niell and Stryker, 2010;Pakan et al, 2016;Saleem et al, 2013).…”