Neuroscience seminars

My lab seeks to understand how the mammalian brain performs the computations that underlie cognitive functions, including decision-making, short-term memory, and spatial navigation, at the level of the building blocks of the nervous system, cell types and neural populations organized into circuits. We have developed methods to measure, manipulate, and analyze neural circuits across various spatial and temporal scales, including technology for virtual reality, optical imaging, optogenetics, intracellular electrophysiology, molecular sensors, and computational modeling. I will present recent work that uses large scale calcium imaging to reveal the functional organization of the mouse posterior cortex for flexible decision-making during spatial navigation in virtual reality. I will also discuss work that uses optogenetics and calcium imaging during a variety of decision-making tasks to highlight how cognitive experience and context greatly alter the cortical circuits necessary for navigation decisions.

The construction of cortical circuits requires the precise formation of connections between excitatory and inhibitory neurons during early development. Multiple factors, including neurotransmitters, neuronal activity, and neuronal-glial interactions, shape how these critical circuits form. Disruptions of these early processes can disrupt circuit formation, leading to epilepsy and other neurodevelopmental disorders. Here, I will describe our work into understanding how prolonged post-natal astrocyte development in the cortex creates a permissive window for glutamate signaling that provides tonic activation of developing interneurons through Grin2D NMDA receptors. Experimental disruption of this pathway results in hyperexcitable cortical circuits and human mutations in the Grin2D gene, as well as other related molecules that regulate early life glutamate signaling, are associated with devastating epileptic encephalopathies. We will explore fundamental mechanisms linking early life glutamate signaling and later circuit hyperexcitability, with an emphasis on potential therapeutic interventions aimed at reducing epilepsy and other neurological dysfunction.

Are the immune system, brain, mind and mood related? Could this explain why chronic low-grade peripheral inflammation is also noted in approximately 1/3 of those with major depressive disorder (MDD)? The field recognized today as immunopsychiatry was founded on scientific evidence that germinated over 30 years ago. Since, it has been understood that (i) there could be a causal link between inflammation and depression, (ii) select blood immune markers show robust potential as biomarkers for inflammation-linked depression, and more generally, (iii) Descartes' theories on mind-body dualism were biologically erroneous. Nonetheless, the mechanistic brain-immune axis in the trinity formulating inflammation-linked depression i.e. psycho-neuro-immunology, still remains unclear. This talk will discuss findings from our recent investigation endeavored to unpack this by linking functional connectivity abnormalities with peripheral immune markers.

We study the dynamics of (inhibitory) balanced networks at varying (i) the level of symmetry in the synaptic connectivity; and (ii) the ariance of the synaptic efficacies (synaptic gain). We find three regimes of activity. For suitably low synaptic gain, regardless of the level of symmetry, there exists a unique stable fixed point. Using a cavity-like approach, we develop a quantitative theory that describes the statistics of the activity in this unique fixed point, and the conditions for its stability. Increasing the synaptic gain, the unique fixed point destabilizes, and the network exhibits chaotic activity for zero or negative levels of symmetry (i.e., random or antisymmetric). Instead, for positive levels of symmetry, there is multi-stability among a large number of marginally stable fixed points. In this regime, ergodicity is broken and the network exhibits non-exponential relaxational dynamics. We discuss the potential relevance of such a “glassy” phase to explain some features of cortical activity.

fMRI results have shown that the supplementary motor area (SMA) and the basal ganglia, most often discussed in their roles in generating action, are engaged by beat-based timing even in the absence of movement. Some have argued that the motor system is “recruited” by beat-based timing tasks due to the presence of motor-like timescales, but a deeper understanding of the roles of these motor structures is lacking. Reviewing a body of motor neurophysiology literature and drawing on the “active inference” framework, I argue that we can see the motor and timing functions of these brain areas as examples of dynamic sub-second prediction informed by sensory event timing. I hypothesize that in both cases, sub-second dynamics in SMA predict the progress of a temporal process outside the brain, and direct pathway activation in basal ganglia selects temporal and sensory predictions for the upcoming interval -- the only difference is that in motor processes, these predictions are made manifest through motor effectors. If we can unify our understanding of beat-based timing and motor control, we can draw on the substantial motor neuroscience literature to make conceptual leaps forward in the study of predictive timing and musical rhythm.

Medium-spiny neurons (MSNs) in the striatum are required for interval timing, or the estimation of the time over several seconds via a motor response. We and others have shown that striatal MSNs can encode the duration of temporal intervals via time-dependent ramping activity, progressive monotonic changes in firing rate preceding behaviorally salient points in time. Here, we investigated how timing-related activity within striatal ensembles changes with experience. We leveraged a rodent-optimized interval timing task in which mice ‘switch’ response ports after an amount of time has passed without reward. We report three main results. First, we found that the proportion of MSNs exhibiting time-dependent modulations of firing rate increased after 10 days of task overtraining. Second, temporal decoding by MSN ensembles increased with experience and was largely driven by time-related ramping activity. Finally, we found that time-related ramping activity generalized across both correct and error trials. These results enhance our understanding of striatal temporal processing by demonstrating that time-dependent activity within MSN ensembles evolves with experience and is dissociable from motor- and reward-related processes.