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Neuronal circuits for emotions in the ventral CA1 hippocampus

Periodic Reporting for period 4 - ventralHippocampus (Neuronal circuits for emotions in the ventral CA1 hippocampus)

Reporting period: 2021-07-01 to 2021-12-31

A fundamental objective in modern neurosciences is to understand the neural mechanisms of learning and memory in both healthy and pathological conditions. The hippocampus is a high-order cortical brain region important for emotions and cognition. The ventral subdivision of the hippocampus (termed anterior hippocampus in humans) is mostly involved in anxiety and contextual fear behaviours.
Pyramidal cells of the CA1 region of the hippocampus represent a main hippocampal output to numerous brains regions relevant for emotional and cognitive processes. The activity and timing of these CA1 pyramidal cells are controlled by a set of very diverse long-range afferent inputs and by local GABAergic interneurons. However, the function of afferent pathways to- and of local GABAergic interneurons in the ventral CA1 hippocampus during contextual fear conditioning and anxiety behaviours have not been investigated so far. We hypothesise that distinct sub-circuits in the ventral CA1 hippocampus differentially contribute to emotional behaviours by diverse and complementary neuronal and network mechanisms.
To test this hypothesis, we are using an innovative cross-level approach combining single-unit recordings and calcium imaging of ventral CA1 GABAergic interneurons and of afferent brain regions to the ventral CA1 hippocampus, selective optogenetic strategies, cell-type-specific viral tracing, juxtacellular recording and labelling from ventral CA1 GABAergic interneurons, and behavioural paradigms in rodents. The proposal is capitalizing on identifying specific neuronal circuits and mechanisms in the ventral CA1 hippocampus to understand how normal and pathological fear and anxiety might arise at the behavioural level. Altogether, we aim to discover logics of cortical computations during emotional behaviour which may lead to translational applications for fear and anxiety disorders in humans.
To investigate the neural mechanisms and circuits of the ventral hippocampus underlying anxiety and contextual fear behaviours, we have implemented multifaceted experimental paradigms relying on activity recordings of identified neuronal cell classes in the ventral hippocampus, selective optogenetic strategies, cell-type-specific viral tracing and behavioural paradigms in rodents. We have identified cell assemblies in the ventral hippocampus reflecting anxiety across different behavioural paradigms and exhibiting sequential activation and enrichment during the experience of anxiety. We have evidence that neural activity within the ventral hippocampus can predict upcoming anxiety behaviour. To understand how anxiety patterns emerge within the ventral hippocampus, we have monitored the activity of local GABAergic interneurons. Consistent with the diversity of GABAergic cell-types within the cerebral cortex, we observed a division of labour among GABAergic neurons during emotional behaviours with parvalbumin-positive interneurons being recruited during innate behaviour (i.e anxiety) but not associative learning. Altogether, our results suggest that selective neural motifs in the ventral hippocampus are recruited during different forms of emotional behaviours and therefore translational approaches targeting specific sub-circuits of the ventral hippocampus could alleviate pathological fear and anxiety in humans.
To understand the computations associated with emotional processing of information in the ventral hippocampus, it is fundamental to investigate how the neural representation of a task can be generalized over ethologically similar paradigms. Hence, we are combining different emotional tasks to characterize the stability and robustness of neural representation during anxiety behaviour. Furthermore, we extend this approach to different forms of negative emotions (i.e. anxiety and fear conditioning) to address the specificity in neural representations across different emotional domains. Since the level of anxiety and conditioned fear behaviours is varying across time and individuals, we are refining the quantification of emotional behaviours using behavioural, physiological and autonomic read-outs.
Neural representations of emotions are ultimately supported by distinct neuronal cell-types interacting together by selective synaptic contacts and neural activity patterns. We hypothesize that distinct emotional paradigms are implemented by the selective recruitment of micro- and large-scale neural circuits of the ventral CA1 hippocampus. The results of our experimental approaches will determine how information is computed within hippocampal circuit motifs to mediate the emergence and the formation of emotional memories.