Optogenetics seminars

Sleep is an active state critical for processing emotional memories encoded during waking in both humans and animals. There is a remarkable overlap between the brain structures and circuits active during sleep, particularly rapid eye-movement (REM) sleep, and the those encoding emotions. Accordingly, disruptions in sleep quality or quantity, including REM sleep, are often associated with, and precede the onset of, nearly all affective psychiatric and mood disorders. In this context, a major biomedical challenge is to better understand the underlying mechanisms of the relationship between (REM) sleep and emotion encoding to improve treatments for mental health. This lecture will summarize our investigation of the cellular and circuit mechanisms underlying sleep architecture, sleep oscillations, and local brain dynamics across sleep-wake states using electrophysiological recordings combined with single-cell calcium imaging or optogenetics. The presentation will detail the discovery of a 'somato-dendritic decoupling'in prefrontal cortex pyramidal neurons underlying REM sleep-dependent stabilization of optimal emotional memory traces. This decoupling reflects a tonic inhibition at the somas of pyramidal cells, occurring simultaneously with a selective disinhibition of their dendritic arbors selectively during REM sleep. Recent findings on REM sleep-dependent subcortical inputs and neuromodulation of this decoupling will be discussed in the context of synaptic plasticity and the optimization of emotional responses in the maintenance of mental health.

Fear learning induces synaptic potentiation between engram neurons in the rat lateral amygdala. This study by Marios Abatis et al. demonstrates how fear conditioning strengthens synaptic connections between engram cells in the lateral amygdala, revealed through optogenetic identification of neuronal ensembles and electrophysiological measurements. The work provides crucial insights into memory formation mechanisms at the synaptic level, with implications for understanding anxiety disorders and developing targeted interventions. Presented by Dr. Kenneth Hayworth, this journal club will explore the paper's methodology linking engram cell reactivation with synaptic plasticity measurements, and discuss implications for memory decoding research.

Recent studies identified memory engram neurons, a neuronal population that is recruited by initial learning and is reactivated during memory recall. Memory engram neurons are connected to one another through memory engram synapses in a distributed network of brain areas. Our central hypothesis is that an associative memory is encoded and consolidated by selective strengthening of engram synapses. We are testing this hypothesis, using a combination of engram cell labeling, optogenetic/chemogenetic, electrophysiological, and virus tracing approaches in rodent models of contextual fear conditioning. In this talk, I will discuss our findings on how synaptic plasticity in memory engram synapses contributes to the acquisition and consolidation of contextual fear memory in a distributed network of the amygdala, hippocampus, and neocortex.

To form a coherent perception of the world around us, we are constantly processing and integrating sensory information from multiple modalities. In fact, when auditory and visual stimuli occur within ~100 ms of each other, individuals tend to perceive the stimuli as a single event, even though they occurred separately. In recent years, our lab, and others, have developed rat models of audiovisual temporal perception using behavioural tasks such as temporal order judgments (TOJs) and synchrony judgments (SJs). While these rodent models demonstrate metrics that are consistent with humans (e.g., perceived simultaneity, temporal acuity), we have sought to confirm whether rodents demonstrate the hallmarks of audiovisual temporal perception, such as predictable shifts in their perception based on experience and sensitivity to alterations in neurochemistry. Ultimately, our findings indicate that rats serve as an excellent model to study the neural mechanisms underlying audiovisual temporal perception, which to date remains relativity unknown. Using our validated translational audiovisual behavioural tasks, in combination with optogenetics, neuropharmacology and in vivo electrophysiology, we aim to uncover the mechanisms by which inhibitory neurotransmission and top-down circuits finely control ones’ perception. This research will significantly advance our understanding of the neuronal circuitry underlying audiovisual temporal perception, and will be the first to establish the role of interneurons in regulating the synchronized neural activity that is thought to contribute to the precise binding of audiovisual stimuli.

Nuo Li (Baylor College of Medicine, USA) shares novel insights into coordinated interhemispheric large-scale neural network activity underpinning short-term memory in mice. Relevant techniques covered include: simultaneous multi-regional recordings using multiple 64-channel H probes during head-fixed behavior in mice. simultaneous optogenetics and population recording. analysis of population recordings to infer interactions between brain regions. Reference: Chen G, Kang B, Lindsey J, Druckmann S, Li N, (2021). Modularity and robustness of frontal cortex networks. Cell, 184(14):3717-3730.

Animals constantly modify their behavior through experience. Flexible behavior is key to our ability to adapt to the ever-changing environment. My laboratory is interested in studying the activity of neuronal ensembles in behaving animals, and how it changes with learning. We have recently set up a paradigm where mice learn to associate sensory information (two different odors) to motor outputs (lick vs no-lick) under head-fixation. We combined this with two-photon calcium imaging, which can monitor the activity of a microcircuit of many tens of neurons simultaneously from a small area of the brain. Imaging the motor cortex during the learning of this task revealed neurons with diverse task-related response types. Intriguingly, different response types were spatially intermingled; even immediately adjacent neurons often had very different response types. As the mouse learned the task under the microscope, the activity coupling of neurons with similar response types specifically increased, even though they are intermingled with neurons with dissimilar response types. This suggests that intermingled subnetworks of functionally-related neurons form in a learning-related way, an observation that became possible with our cutting-edge technique combining imaging and behavior. We are working to extend this study. How plastic are neuronal microcircuits during other forms of learning? How plastic are they in other parts of the brain? What are the cellular and molecular mechanisms of the microcircuit plasticity? Are the observed activity and plasticity required for learning? How does the activity of identified individual neurons change over days to weeks? We are asking these questions, combining a variety of techniques including in vivo two-photon imaging, optogenetics, electrophysiology, genetics and behavior.

Coping with threatening situations requires both identifying stimuli predicting danger and selecting adaptive behavioral responses in order to survive. The dorso medial prefrontal cortex (dmPFC) is a critical structure involved in the regulation of threat-related behaviour, yet it is still largely unclear how threat-predicting stimuli and defensive behaviours are associated within prefrontal networks in order to successfully drive adaptive responses. To address these questions, we used a combination of extracellular recordings, neuronal decoding approaches, and optogenetic manipulations to show that threat representations and the initiation of avoidance behaviour are dynamically encoded in the overall population activity of dmPFC neurons. These data indicate that although dmPFC population activity at stimulus onset encodes sustained threat representations and discriminates threat- from non-threat cues, it does not predict action outcome. In contrast, transient dmPFC population activity prior to action initiation reliably predicts avoided from non-avoided trials. Accordingly, optogenetic inhibition of prefrontal activity critically constrained the selection of adaptive defensive responses in a time-dependent manner. These results reveal that the adaptive selection of active fear responses relies on a dynamic process of information linking threats with defensive actions unfolding within prefrontal networks.