Physiology seminars

How the brain creates a painful experience remains a mystery. Solving this mystery is crucial to understanding the fundamental biological processes that underlie the perception of body integrity, and to creating better, non-addictive pain treatments. My laboratory’s goal is to resolve the neural basis of pain. We aim to understand the mechanisms by which our nervous system produces and assembles the sensory-discriminative, affective-motivational, and cognitive-evaluative dimensions of pain to create this unique and critically important experience. To capture every component of the pain experience, we examine the entirety of the pain circuitry, from sensory and spinal ascending pathways to cortical/subcortical circuits and brainstem descending pain modulation systems, at the molecular, cellular, circuit and whole-animal levels. For these studies, we have invented novel behavioral paradigms to interrogate the affective and cognitive dimensions of pain in mice while simultaneously imaging and manipulating nociceptive circuits. My laboratory also investigates how opioids suppress pain. Remarkably, despite their medical and societal significance, how opium poppy alkaloids such as morphine produce profound analgesia remains largely unexplained. By identifying where and how opioids act in neural circuits, we not only establish the mechanisms of action of one of the oldest drugs known to humans, but also reveal the critical elements of the pain circuitry for developing of novel analgesics and bringing an end to the opioid epidemic.

Sensory experience and perceptual learning changes receptive field properties of cortical pyramidal neurons possibly mediated by long-term potentiation (LTP) of synapses. We have previously shown in the mouse somatosensory cortex (S1) that sensory-driven LTP in layer (L) 2/3 pyramidal neurons is dependent on higher order thalamic feedback from the posteromedial nucleus (POm), which is thought to convey contextual information from various cortical regions integrated with sensory input. We have followed up on this work by dissecting the cortical microcircuitry that underlies this form of LTP. We found that repeated pairing of Pom thalamocortical and intracortical pathway activity in brain slices induces NMDAr-dependent LTP of the L2/3 synapses that are driven by the intracortical pathway. Repeated pairing also recruits activity of vasoactive intestinal peptide (VIP) interneurons, whereas it reduces the activity of somatostatin (SST) interneurons. VIP interneuron-mediated inhibition of SST interneurons has been established as a motif for the disinhibition of pyramidal neurons. By chemogenetic interrogation we found that activation of this disinhibitory microcircuit motif by higher-order thalamic feedback is indispensable for eliciting LTP. Preliminary results in vivo suggest that VIP neuron activity also increases during sensory-evoked LTP. Together, this suggests that the higherorder thalamocortical feedback may help modifying the strength of synaptic circuits that process first-order sensory information in S1. To start characterizing the relationship between higher-order feedback and cortical plasticity during learning in vivo, we adapted a perceptual learning paradigm in which head-fixed mice have to discriminate two types of textures in order to obtain a reward. POm axons or L2/3 pyramidal neurons labeled with the genetically encoded calcium indicator GCaMP6s were imaged during the acquisition of this task as well as the subsequent learning of a new discrimination rule. We found that a subpopulation of the POm axons and L2/3 neurons dynamically represent textures. Moreover, upon a change in reward contingencies, a fraction of the L2/3 neurons re-tune their selectivity to the texture that is newly associated with the reward. Altogether, our data indicates that higher-order thalamic feedback can facilitate synaptic plasticity and may be implicated in dynamic sensory stimulus representations in S1, which depends on higher-order features that are associated with the stimuli.