Faculty Bibliography

Mother-infant bonding develops rapidly following parturition and is accompanied by changes in sensory perception and behavior. Here, we study how ultrasonic vocalizations (USVs) are represented in the brain of mothers. Using a mouse line that allows temporally controlled genetic access to active neurons, we find that the temporal association cortex (TeA) in mothers exhibits robust USV responses. Rabies tracing from USV-responsive neurons reveals extensive subcortical and cortical inputs into TeA. A particularly dominant cortical source of inputs is the primary auditory cortex (A1), suggesting strong A1-to-TeA connectivity. Chemogenetic silencing of USV-responsive neurons in TeA impairs auditory-driven maternal preference in a pup-retrieval assay. Furthermore, dense extracellular recordings from awake mice reveal changes of both single-neuron and population responses to USVs in TeA, improving discriminability of pup calls in mothers compared with naive females. These data indicate that TeA plays a key role in encoding and perceiving pup cries during motherhood.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Excitation in neural circuits must be carefully controlled by inhibition to regulate information processing and network excitability. During development, cortical inhibitory and excitatory inputs are initially mismatched but become co-tuned or balanced with experience. However, little is known about how excitatory-inhibitory balance is defined at most synapses or about the mechanisms for establishing or maintaining this balance at specific set points. Here we show how coordinated long-term plasticity calibrates populations of excitatory-inhibitory inputs onto mouse auditory cortical pyramidal neurons. Pairing pre- and postsynaptic activity induced plasticity at paired inputs and different forms of heterosynaptic plasticity at the strongest unpaired synapses, which required minutes of activity and dendritic Ca²⁺ signaling to be computed. Theoretical analyses demonstrated how the relative rate of heterosynaptic plasticity could normalize and stabilize synaptic strengths to achieve any possible excitatory-inhibitory correlation. Thus, excitatory-inhibitory balance is dynamic and cell specific, determined by distinct plasticity rules across multiple excitatory and inhibitory synapses.

In humans and animal models, oxytocin increases social closeness, attachment and prosocial behaviors, while decreasing anxiety and stress levels. Efficiently triggering the release of endogenous oxytocin could serve as a powerful therapeutic intervention for disorders of social behavior and for anxiety. We designed a new version of a social sensorimotor synchronization task to investigate the role of social approval in inducing biochemical and psychological changes following behavioral synchrony in a sample of 80 college students. Social approval in the form of real time positive feedback increased well-being only in women, while increasing social closeness in both genders. Social disapproval in the form of real time negative feedback prevented a decrease in stress levels that otherwise women reported following engagement in either social or non-social synchronization. Surprisingly, for certain personality traits, negative social feedback during sensorimotor synchronization was psychologically beneficial irrespective of gender. Salivary oxytocin levels increased only in women after the social but not the non-social synchronization tasks. Oxytocin dynamics were independent of the type of real time feedback that subjects received, indicating the existence of distinct mechanisms for hormonal versus behavioral changes following synchronization. Nevertheless, changes in salivary oxytocin after positive social feedback correlated with changes in well-being and predicted changes in prosocial attitudes. Our findings show evidence of distinct mechanisms for behavioral versus hormonal changes following social sensorimotor synchronization, and indicate that gender and personality traits should be carefully considered when designing behavioral therapies for improving social attitudes and for stress management.

Cochlear implants are one of the most successful neuroprosthetic devices that have been developed to date. Profoundly deaf patients can achieve speech perception after complete loss of sensory input. Despite the improvements many patients experience, there is still a large degree of outcome variability. It has been proposed that central plasticity may be a major factor in the different levels of benefit that patients experience. However, the neural mechanisms of how plasticity impacts cochlear implant learning and the degree of plasticity's influence remain unknown. Here, we review the human and animal research on three of the main ways that central plasticity affects cochlear implant outcomes.

Performance on cognitive tasks during learning is used to measure knowledge, yet it remains controversial since such testing is susceptible to contextual factors. To what extent does performance during learning depend on the testing context, rather than underlying knowledge? We trained mice, rats and ferrets on a range of tasks to examine how testing context impacts the acquisition of knowledge versus its expression. We interleaved reinforced trials with probe trials in which we omitted reinforcement. Across tasks, each animal species performed remarkably better in probe trials during learning and inter-animal variability was strikingly reduced. Reinforcement feedback is thus critical for learning-related behavioral improvements but, paradoxically masks the expression of underlying knowledge. We capture these results with a network model in which learning occurs during reinforced trials while context modulates only the read-out parameters. Probing learning by omitting reinforcement thus uncovers latent knowledge and identifies context- not "smartness"- as the major source of individual variability.

Statistical learning has been proposed as a possible mechanism by which individuals can become sensitive to the structures of language fundamental for speech perception. Since its description in human infants, statistical learning has been described in human adults and several non-human species as a general process by which animals learn about stimulus-relevant statistics. The neurobiology of statistical learning is beginning to be understood, but many questions remain about the underlying mechanisms. Why is the developing brain particularly sensitive to stimulus and environmental statistics, and what neural processes are engaged in the adult brain to enable learning from statistical regularities in the absence of external reward or instruction? This review will survey the statistical learning abilities of humans and non-human animals with a particular focus on communicative vocalizations. We discuss the neurobiological basis of statistical learning, and specifically what can be learned by exploring this process in both humans and laboratory animals. Finally, we describe advantages of studying vocal communication in rodents as a means to further our understanding of the cortical plasticity mechanisms engaged during statistical learning. We examine the use of rodents in the context of pup retrieval, which is an auditory-based and experience-dependent form of maternal behavior.

Neural representations of the external world are constructed and updated in a manner that depends on behavioral context. For neocortical networks, this contextual information is relayed by a diverse range of neuromodulatory systems, which govern attention and signal the value of internal state variables such as arousal, motivation, and stress. Neuromodulators enable cortical circuits to differentially process specific stimuli and modify synaptic strengths in order to maintain short- or long-term memory traces of significant perceptual events and behavioral episodes. One of the most important subcortical neuromodulatory systems for attention and arousal is the noradrenergic locus coeruleus. Here we report that the noradrenergic system can enhance behavior in rats performing a self-initiated auditory recognition task, and optogenetic stimulation of noradrenergic locus coeruleus neurons accelerated the rate at which trained rats began correctly responding to a change in reward contingency. Animals successively progressed through distinct behavioral epochs, including periods of perseverance and exploration that occurred much more rapidly when animals received locus coeruleus stimulation. In parallel, we made recordings from primary auditory cortex and found that pairing tones with locus coeruleus stimulation led to a similar set of changes to cortical tuning profiles. Thus both behavioral and neural responses go through phases of adjustment for exploring and exploiting environmental reward contingencies. Furthermore, behavioral engagement does not necessarily recruit optimal locus coeruleus activity.

Introduction: Vagus nerve stimulation is currently used as a medical treatment for those suffering from severe epilepsy or depression, but the mechanisms underlying vagus nerve stimulation are poorly understood. The vagus nerve helps connect essentially all peripheral organs to the central nervous system, sending afferents to the nucleus tractus solitarius. Recent studies indicate that vagus nerve stimulation can produce long-lasting plasticity in the cerebral cortex, leading to improved sensory processing and recovery of motor behavior after stroke (Boreland et al, Brain Stimul (2016). An understanding of the circuit mechanisms by which vagus nerve stimulation can produce these results would be important for enhancing behavioral outcomes and developing less invasive or non-invasive neuromodulatory therapeutic techniques. Method(s): Studies in mice provide an opportunity for monitoring and manipulating various aspects of neural circuits involved in behavior. One difficulty in the mouse model is the lack of vagus nerve cuff electrodes given the small size of the mouse vagus nerve. We first built a novel vagus nerve cuff electrode for mice and demonstrated reliable low-impedance recordings and stimulation during behavior in mice chronically implanted for months. Two-photon imaging of the auditory cortex was used to track neural responses to tones paired with vagus nerve stimulation. Animals are then trained on either a paired go/no-go or two-alternative forced choice auditory detection and recognition task (Martins and Froemke, Nat Neurosci 2015; Kuchibhotla et al. Nat Neurosci 2017). Result(s): Stimulation of the vagus nerve was calibrated to transiently reduce respiration without affecting other physiological processes (e.g., heart rate). Using two-photon imaging, we found that pairing target tones with vagus nerve stimulation for five minutes led to a short-term enhancement of sensory responses in the mouse auditory cortex. After several days of these brief 5-minute pairing sessions, long-term plasticity was observed with increases in representation of the target tone for at least days thereafter. Conclusion(s): These changes are reminiscent of the effects of basal forebrain stimulation (Froemke et al. Nature 2007) and we are now investigating how vagus nerve stimulation might lead to direct or indirect activation of central modulatory systems to improve plasticity and behavior in mice.

Introduction: The mammalian enteric nervous system (ENS) regulates intestinal function in response to luminal changes in nutrients and microbiota. The ENS also modulates immune cells to control microbial homeostasis and fight infections. Enteric neurons signal to the brain via the vagus nerve, providing a mechanism by which microbiota can influence neural activity and behavior at homeostasis or during infections with gut pathogens. However, little is known about the relation between vagus nerve activity and 'sickness behaviors' such as decreased attention, increased irritability and depression, and decreased interest and energy. Here we aimed to record vagus nerve responses in behaving animals towards understanding this gut-brain signaling connection in sickness behavior. Method(s): Custom nerve cuff electrodes were used to monitor vagus nerve activity of wild-type male mice. Cuffs were made with 0.2 mm micro-renathane tubing to surround the upper branch of the sensory vagus nerve and connected to socket gold pins and medwire. Chronic nerve cuffs were implanted in mice aged 6-12 weeks. Surgery consisted of securing gold pins to the cranial vertex and connecting electrodes to the vagus nerve in the neck, around which the cuff was placed. The grounding wire was secured near the cuff. One to two weeks post-surgery, each mouse underwent sickness induction via lipopolysaccharide (LPS) injection. LPS solution was formulated with 9.5/g muL of 0.9% saline solution and 0.5/g muL of pure LPS via intraperitoneal injection. Electrophysiological activity of the vagus nerve was recorded together with video monitoring of behavior, prior to injection to first establish a baseline, and post-injection activity was recorded for up to 24 hours. Sickness behavior was ethogrammed and neural activity analyzed in each animal. Result(s): LPS injection led to reduction of several different behaviors including overall motion in the homecage for hours afterwards. Analysis of simultaneously-recorded vagus activity is ongoing. Conclusion(s): We here describe an integrated system that combines long-term videography and behavioral analysis with recordings of the peripheral nerve activity using a custom chronic nerve cuff for the mouse vagus. Using this system, we have begun to relate neural activity in the sensory vagus to physiological state and behavioral changes in mice for the first time.