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.

Dysregulation of emotional processing and its integration with cognitive functions are central features of many mental/emotional disorders associated both with externalizing problems (aggressive, antisocial behaviors) and internalizing problems (anxiety, depression). As Dr. Joseph LeDoux, our invited speaker of this program, wrote in his famous book “Synaptic self: How Our Brains Become Who We Are”—the brain’s synapses—are the channels through which we think, act, imagine, feel, and remember. Synapses encode the essence of personality, enabling each of us to function as a distinctive, integrated individual from moment to moment. Thus, exploring the functioning of synapses leads to the understanding of the mechanism of (patho)physiological function of our brain. In this context, we have investigated the pathophysiology of psychiatric disorders, with particular emphasis on the synaptic function of model mice of various psychiatric disorders such as schizophrenia, autism, depression, and PTSD. Our current interest is how synaptic inputs are integrated to generate the action potential. Because the spatiotemporal organization of neuronal firing is crucial for information processing, but how thousands of inputs to the dendritic spines drive the firing remains a central question in neuroscience. We identified a distinct pattern of synaptic integration in the disease-related models, in which extra-large (XL) spines generate NMDA spikes within these spines, which was sufficient to drive neuronal firing. We experimentally and theoretically observed that XL spines negatively correlated with working memory. Our work offers a whole new concept for dendritic computation and network dynamics, and the understanding of psychiatric research will be greatly reconsidered. The second half of my talk is the development of a novel synaptic tool. Because, no matter how beautifully we can illuminate the spine morphology and how accurately we can quantify the synaptic integration, the links between synapse and brain function remain correlational. In order to challenge the causal relationship between synapse and brain function, we established AS-PaRac1, which is unique not only because it can specifically label and manipulate the recently potentiated dendritic spine (Hayashi-Takagi et al, 2015, Nature). With use of AS-PaRac1, we developed an activity-dependent simultaneous labeling of the presynaptic bouton and the potentiated spines to establish “functional connectomics” in a synaptic resolution. When we apply this new imaging method for PTSD model mice, we identified a completely new functional neural circuit of brain region A→B→C with a very strong S/N in the PTSD model mice. This novel tool of “functional connectomics” and its photo-manipulation could open up new areas of emotional/psychiatric research, and by extension, shed light on the neural networks that determine who we are.

A long-term treatment with antidepressants reduces the risk to develop AD and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently studied for their neuroprotective properties in AD. An impairment of neurotrophic factors signaling seems to be a common pathophysiological event in depression and AD. In particular a deficit of transforming growth factor-β1 (TGF-β1) and increased oxidative stress have been found both in depression and AD. In the present work the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype in a non-transgenic mouse model of AD (i.c.v. Aβ1-42 injection) by rescue of TGF-β1 signaling. The same drugs were also tested for their ability to modulate the expression of pro-oxidant genes as well as of genes related to the antioxidant machinery.