Optogenetics seminars

The neural correlates of decision-making have been investigated extensively, and recent work aims to identify under what conditions cortex is actually necessary for making accurate decisions. We discovered that mice with distinct cognitive experiences, beyond sensory and motor learning, use different cortical areas and neural activity patterns to solve the same task, revealing past learning as a critical determinant of whether cortex is necessary for decision tasks. We used optogenetics and calcium imaging to study the necessity and neural activity of multiple cortical areas in mice with different training histories. Posterior parietal cortex and retrosplenial cortex were mostly dispensable for accurate performance of a simple navigation-based visual discrimination task. In contrast, these areas were essential for the same simple task when mice were previously trained on complex tasks with delay periods or association switches. Multi-area calcium imaging showed that, in mice with complex-task experience, single-neuron activity had higher selectivity and neuron-neuron correlations were weaker, leading to codes with higher task information. Therefore, past experience is a key factor in determining whether cortical areas have a causal role in decision tasks.

Transient changes in dopamine activity in response to reward and punishment have been known to regulate reward-related learning. However, the cellular basis that detects the transient dopamine signaling has long been unclear. Using two-photon microscopy and optogenetics, I have shown that transient increases and decreases of dopamine modulate plasticity of dopamine D1 and D2 receptor-expressing cells in the nucleus accumbens, respectively. At the behavioral level, I characterized that these D1 and D2 cells cooperatively tune learning by generalization and discrimination learning. Interestingly, disturbance of the dopamine signaling impaired D2 cell plasticity and discrimination learning, which was analogous to salience misattribution seen in subjects with schizophrenia.

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.

Over 60 years of research has established that medial temporal lobe structures, including the hippocampus and entorhinal cortex, are necessary for the formation of episodic memories (i.e. memories of specific personal events that occur in spatial and temporal context). While prior work to establish the neural mechanisms underlying episodic memory has largely focused on questions related spatial context, recently we have begun to investigate how these brain structures could be involved in encoding aspects of temporal context. In particular, we have focused on how medial entorhinal cortex, a structure well known for its role in spatial memory, may also be involved in encoding interval time. To answer this question we have developed an instrumental paradigm for head-fixed mice that requires both immobile interval timing and locomotion-dependent navigation behavior. By combining this behavioral paradigm with large-scale cellular resolution functional imaging and optogenetic-mediated inactivation, our results suggest that MEC is required for learning of interval timing behavior and that interval timing could be mediated through regular, sequential neural activity of a distinct subpopulation of neurons in MEC that encode elapsed time during periods of immobility (Heys and Dombeck, 2018; Heys et al, 2020; Issa et al., 2020). In this talk, I will discuss these findings and discuss our on-going work to investigate the principles underlying the role of medial temporal lobe structures in timing behavior and episodic memory.

Sequential temporal ordering and patterning are key features of natural signals, used by the brain to decode stimuli and perceive them as sensory objects. Touch is one sensory modality where temporal patterning carries key information, and the rodent whisker system is a prominent model for understanding neuronal coding and plasticity underlying touch sensation. Neurons in this system are precise encoders of fluctuations in whisker dynamics down to a timescale of milliseconds, but it is not clear whether they can refine their encoding abilities as a result of learning patterned stimuli. For example, can they enhance temporal integration to become better at distinguishing sequences? To explore how cortical coding plasticity underpins sequence discrimination, we developed a task in which mice distinguished between tactile ‘word’ sequences constructed from distinct vibrations delivered to the whiskers, assembled in different orders. Animals licked to report the presence of the target sequence. Optogenetic inactivation showed that the somatosensory cortex was necessary for sequence discrimination. Two-photon imaging in layer 2/3 of the primary somatosensory “barrel” cortex (S1bf) revealed that, in well-trained animals, neurons had heterogeneous selectivity to multiple task variables including not just sensory input but also the animal’s action decision and the trial outcome (presence or absence of the predicted reward). Many neurons were activated preceding goal-directed licking, thus reflecting the animal’s learnt action in response to the target sequence; these neurons were found as soon as mice learned to associate the rewarded sequence with licking. In contrast, learning evoked smaller changes in sensory response tuning: neurons responding to stimulus features were already found in naïve mice, and training did not generate neurons with enhanced temporal integration or categorical responses. Therefore, in S1bf sequence learning results in neurons whose activity reflects the learnt association between target sequence and licking, rather than a refined representation of sensory features. Taken together with results from other laboratories, our findings suggest that neurons in sensory cortex are involved in task-specific processing and that an animal does not sense the world independently of what it needs to feel in order to guide behaviour.