Robert Froemke - US grants

DESCRIPTION (provided by applicant): The goal of this proposal is to directly examine the relation between adult cortical synaptic plasticity and perceptual learning. In the first (mentored) part of this proposal, I will utilize a prosthetic device for electrical stimulation and recording, and learn to perform behavioral experiments and make recordings in awake animals. In the second (independent) part, I will use whole-cell and extracellular recording in vivo and in slices of primary auditory cortex (A1) to reveal the neural correlates, mechanisms, and network dynamics involved in learning the significance of sensory input. The mammalian auditory system is plastic, maintaining the capacity for structural and functional reorganization all throughout life. Plasticity is an important feature of A1, especially for processing the behavioral significance of sensory signals such as speech, music and other forms of auditory communication. Mechanisms of cortical plasticity are disrupted in learning impairments and language disorders;conversely, engaging these mechanisms by training programs and prosthetic devices will help repair damaged brains in pathological conditions. Thus understanding the rules, cellular mechanisms, and functional relevance of cortical plasticity is essential for language learning and mental health. Patterns of sensory input control the organization and plasticity of cortical receptive fields, depending on activation of excitatory and inhibitory circuits. Subcortical neuromodulator systems are also necessary for cortical plasticity, reflecting the importance of attention and behavioral context for learning. Behaviorally- engaged neuromodulators have a wide range of effects in cortex and throughout the rest of the brain, raising the questions of how attention and neuromodulation govern cortical networks to induce modification of these circuits, and how such changes in turn affect auditory perception and behavior. In this proposal, I will perform behavioral and electrophysiological experiments to determine the mechanisms and functional significance of A1 plasticity in adult rats. I will thoroughly examine A1 plasticity at the synaptic, network, and behavioral levels to provide a unified description of the neural correlates of perceptual learning.

Maternal care of offspring requires rapid neurobehavioral changes, including plasticity within circuits specialized for processing infant cues such as crying. Neuroendocrine signals are important for neuroplasticity, including release of the peptide hormone oxytocin. Oxytocin is released from the hypothalamus and is important for childbirth and lactation. Oxytocin also acts in the brain where it is believed to increase the salience of social information, enhancing pair bonding and maternal behavior. Clinical studies suggest that oxytocin is a promising therapeutic agent, with patients sometimes engaging more successfully in social interactions. There is a high rate of child maltreatment and neglect, but training programs and interventions that teach parents to detect and respond to social signals have had some success. These therapies would benefit from understanding the interactions between infant social cues, oxytocin modulation, and neuroplasticity relevant for maternal behaviors. In this proposal, we will study the neural circuitry, plasticity, and behavioral effects of oxytocin in the context of maternal behavior in mice. We study neurobehavioral responses to infant ultrasonic vocalizations by maternal caregivers, which requires experience with pups and is facilitated by oxytocin. We will study the sequence of auditory-based maternal behaviors first expressed by pup-naïve females co-housed with mothers and pups. The central hypothesis is that social contact with dam or pups releases oxytocin, interacting with pup calls to induce plasticity in auditory cortex. We will use in vivo recording and imaging, combined with behavior and optogenetics to examine how cortex is modified by oxytocin and pup call sounds, building on our past work on cortical plasticity and modulation. In Aim 1 we measure activity in auditory cortex during co-housing, relating retrieval behavior to cortical plasticity. In Aim 2, we examine the how oxytocin modulates excitatory and inhibitory cells and synapses for processing auditory social signals. Finally in Aim 3 we ask how oxytocin is appropriately released by infant cues, to initiate these auditory cortical changes and shape maternal behavior in newly- maternal mice. In summary, here we will use behavioral experiments combined with optogenetics and in vivo recordings to ask how oxytocin is released and affects auditory cortex, to enable maternal recognition of infant distress calls. These experiments will provide fundamental and urgently-needed data on the neural circuitry and functional consequences of oxytocin signaling in the mammalian brain, in the context of a deep and long-standing question in neuroscience: how are specific neural circuits specialized for sensory processing and maternal behavior?

Project Summary Cortical inhibitory cells are critical for regulating information processing and synaptic plasticity in neural circuits. This plasticity is essential for learning and memory, and is an important feature of the auditory cortex, especially for learning the significance of sensory signals such as speech. Long-term synaptic plasticity requires sensory experience and activation of neuromodulatory systems such as the cholinergic nucleus basalis, which conveys behavioral context to local cortical circuits. However, little is known about how cortical interneurons are involved in these mechanisms, or if different inhibitory cell types have different roles for developmental or adult plasticity. Recently we developed an approach to measure long-term excitatory and inhibitory synaptic modifications in vivo over hours to weeks. These experiments revealed that prior to experience with sounds, cortical inhibition was initially mismatched with excitation, but becomes `balanced' with excitation after experience or training. [These experiments now allow us to construct a new framework for understanding the roles of 5HT3aR and non-5HT3aR cortical interneurons during auditory behavior in mice, with a series of behavioral, imaging, and recording experiments integrated with the larger collaborative PPG structure. We hypothesize that there are important functional differences in these cell types, in terms of their relative contributions to auditory behavior (Aim 1), cholinergic modulation (Aim 2), and cortical microcircuit organization and plasticity (Aim 3). Specifically, in Aim 1 we will first examine the behavioral relevance of specific cortical interneuron subtypes, as initially-naive mice are trained to perform an auditory detection and recognition task we have used in the lab for years. We ask how sensory experience and behavioral training might recruit these cell types and naturally shape excitatory and inhibitory circuit elements, using whole-cell recordings combined with 2-photon Ca2+ imaging to directly measure excitation and various cell-type-specific sources of inhibition in vivo. In Aim 2 we examine if these cell types are differentially affected by cholinergic modulation, perhaps due to differential sensitivity to acetylcholine or specific wiring of cholinergic input into cortex. Finally, in Aim 3 we will make recordings in cortical brain slices, to document how different cortical interneuron types are synaptically connected and modified for circuit operation.] In summary, here we will use in vivo and in vitro electrophysiology, imaging, and optogenetics to ask how different cortical interneurons (5HT3aR vs non-5HT3aR) govern sensory processing and plasticity. The two core concepts of these studies involve long-term synaptic plasticity, believed to be a major neural correlate of learning and memory, and excitatory-inhibitory balance- the precise regulation of excitation by inhibitory circuits. These processes are believed to be disrupted in a large number of neurological conditions and mental health disorders, highlighting an urgent need for a more complete description of cortical organization and function during behavior.

Project Summary (Project 1, Co-PIs: Froemke, Lin, Buzsaki) Oxytocin is a neuropeptide important for social behavior, such as maternal care and pair bonding. It is now believed that direct axonal oxytocin release into various forebrain targets is critical for social behavior, but it remains unclear where and when oxytocin modulation is required to enhance social information processing and regulate maternal behavior. Oxytocin is essential for nursing, but it is unclear what other aspects of maternal behavior by mothers or unrelated co-caring animals depend on the oxytocin system. Oxytocin administration might also be clinically promising, improving outcomes in autism spectrum disorders, social anxiety, and post- partum depression. However, it is imperative to understand the functional anatomy and whole-brain neural circuitry by which oxytocin affects behavioral changes, including when oxytocin might be released, and whether there are differences in oxytocin modulation that depend on gender or social context. Here we will address this critical knowledge gap. Recently, we generated the first specific antibodies to the mouse oxytocin receptor, used these antibodies to determine where these receptors are localized, and examined how oxytocin can enable pup retrieval behavior in maternal mice. Those previous studies provide a robust foundation for the current Project, in which our team aims to understand which target neural circuits are modulated by oxytocin, and if there are behavioral episodes that might be sensitive to oxytocin modulation during brief periods of social interaction. The central hypothesis is that oxytocin is absolutely necessary to initiate maternal behaviors in key areas including auditory cortex and hippocampus, but may be dispensable in experienced mothers. We will perform behavioral, optogenetic, and circuit mapping studies in adult mice to determine where and when oxytocin modulates neural circuits to enhance social information processing and subsequently improve maternal behavior. In Aim 1 we will build a new behavioral recording system to continuously monitor social interactions for days to weeks. In Aim 2, we profile oxytocin projections and oxytocin receptor expression throughout the entire adult brain to find potential hotspots of modulation. Finally in Aims 3 and 4, we perform optogenetic loss-of-function and gain-of-function type experiments to determine where and when oxytocin modulation is needed for maternal behavior or at what points might additional oxytocin release accelerate maternal behavior onset or improve steady-state performance. In summary, here we will study the emergence of social interactions and maternal behaviors as they are naturally expressed during multiple animal co-housing, using a new behavioral monitoring systems we will build. We will then use this system to determine when and where oxytocin modulation is required and most effective at promoting pro-social interactions and child care.

Summary Neuroscience has an essential requirement for large-scale perturbation tools. Such tools would be transformative in the mapping of brain function, the causal testing of neurotheoretic models, and the diagnosis and treatment of neurological disorders. The proposed five-year project is aimed at uncovering the fundamental mechanisms of US stimulation through the reciprocity of mathematical analysis, computational modeling and experimental validation. Using a previously developed predicative model as a scaffold, we will build a full explanatory theory of US stimulation effects in mice, including cell-type specific effects of this perturbation modality. A large parameter space of US variables will be explored, including spatiotemporal dynamics and duty cycle modulation, while sensitive two-photon functional imaging metrics will be used to measure the biophysical impact of these parameters on neural responses in the cortex, thalamus, and hippocampus in vivo.