Understanding Circuits

SUMMARY The brain transforms raw sensory input into perception and cognition, and this transformation relies on computations performed across neuronal circuits. Fortunately, the anatomy of cortical microcircuits in non- human primate models is much better understood today than decades ago. Indeed, sensory information travels in the cerebral cortex along feedforward and feedback pathways. While bottom-up feedforward connections have been extensively examined over the past several decades, the functional role of feedback projections continues to remain mysterious.

Project Summary The function of the nervous system is dependent on complex interactions between networks of neurons composed of multiple neuron types. Understanding how these networks function both in health and disease is dependent on understanding the precise connectivity between specific neuron types and their functional interactions in the intact brain.

PROJECT ABSTRACT Recent advances in microscopy permit volume imaging - the near-simultaneous imaging of many neurons in a circuit - with 2-photon (2P) excitation, yielding new insights into the circuits underlying relatively simple behaviors. Volume imaging techniques and 2P excitation have been limited mainly to small animals such as rodents, including studies of mouse cortex.

Project Summary Opioids as a pain medication has been the most preferred pain treatments in order to provide quick relief from severe pain. Decades of opioid abuse have triggered negative impact on pain therapies. Understanding of neural circuits that are actually driving pain is essential in order to develop more effective and safer pain therapies. Neuroanatomical studies have allowed us to define the regions and subsets of neurons that are important for pain.

ABSTRACT: The lateral habenula (LHb) impacts motivated behavior through dense direct and indirect projections to midbrain dopaminergic and serotonergic neurons. Some LHb neurons project directly to midbrain dopaminergic or serotonergic neurons; others project indirectly through one of multiple types of midbrain GABAergic neurons. Similar to dopaminergic neurons, the LHb encodes reward prediction error (RPE) - the discrepancy between expected and actual value – a powerful computation that guides learning from environmental feedback.

PROJECT SUMMARY When Confucius said, “Tell me who are your friends, and I’ll tell you who you are,” he was noticing that how we behave and communicate is shaped by who we choose to hang out with every day. We constantly mimic the mannerisms and behaviors of friends and loved ones. Yet the neural basis of how we imitate, and more importantly who we choose to emulate and why, is largely unknown. Parrots provide a powerful yet untapped model system for social learning.

Project summary Although single neurons occasionally project to a single downstream target, it is more often the case that their axons collateralize and project to multiple distinct anatomical areas. This feature of neuroanatomy has been appreciated for over 100 years and is theorized to be critical to coordinating brain-wide states. Despite this, collateral projections have largely been overlooked in contemporary neuroscience.

Summary Genetic technologies have revolutionized the way scientists can dissect out brain circuitry by inserting G protein-coupled receptors that enable selective modulation of neurons in target structures. Amongst them, a promising tool,DREADDS (designer receptors exclusively activated by designer drugs) is used to modulate neural activity pharmacologically in targeted brain regions. Unfortunately, DREADDS also require invasive methods to deliver the genes that express the receptor.

Summary Strategic behaviors often take account of uncertainty. For example, if we are presented with two conflicting pieces of information, we give less weight to the more uncertain source of information – i.e., the source of information that leads to lower accuracy overall. Notably, even insects behave as if they make strategic use of their own uncertainty. Importantly, the neural correlates of uncertainty are essentially unknown. In this collaborative project, we will use modeling and neural imaging to identify the neural correlates of uncertainty.

Project Summary / Abstract Systems neuroscience has viewed the brainstem noradrenergic nucleus, Locus Coeruleus (LC), as the source of a global arousal signal, which modulates cognitive functions by altering operations throughout the entire central nervous system. This is achieved, presumably, by this small collection of only ~1,600 neurons in rodents spiking synchronously.