Faculty Bibliography

BACKGROUND:TDP-43 pathology is linked to cognitive deficits in diverse neurodegenerative disorders, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). The effects of TDP-43 pathology in different cell types, including astrocytes, are not clear. METHOD/METHODS:In this study, we used postmortem human brain samples, extensive behavioral testing in numerous cohorts of doubly transgenic mice, gene profiling in different isolated brain regions and cells, glial-neuronal co-culture assays and physiology, and biochemical assays to identify specific signaling cascades linked to TDP-43. RESULT/RESULTS:Our results show that astrocytic TDP-43 is mislocalized in postmortem human hippocampal tissue from AD cases. To assess the effects of widespread or hippocampus specific dysregulation of astrocytic TDP-43 in complementary systems, we generated three novel astrocyte specific mouse models of TDP-43 dysfunction. Consistently, these mouse models indicated that astrocytic TDP-43 dysfunction causes progressive hippocampus-dependent memory loss, but not motor deficits. Manipulation of astrocytic TDP-43 also increased hippocampal levels of interferon -inducible chemokines CXCL9 and CXCL10, and altered cell-autonomous antiviral signaling and defense against viral pathogens. Moreover, expression of CXCR3, the shared receptor for CXCL9 and CXCL10, was increased selectively in hippocampal presynaptic terminals. Acute or chronic stimulation of presynaptic CXCR3 modulated neuronal activities and presynaptic vesicles. CONCLUSION/CONCLUSIONS:Overall, our findings shed new light on TDP-43 dysregulation in astrocytes and its potential contributions to disease-related impairments in cognitive and immune-related functions. We report a novel chemokine-mediated astrocytic-neuronal pathway that is likely downstream of aberrant antiviral immune signaling in astrocytes that affects presynaptic release and neuronal activities. Together, these results implicate astrocytic TDP-43 dysregulation in the pathogenesis of dementia and point to chemokine signaling and CXCR3 as potential therapeutic targets for alleviating cognitive decline.

Maternal care, including by non-biological parents, is important for offspring survival^1-8. Oxytocin^1,2,9-15, which is released by the hypothalamic paraventricular nucleus (PVN), is a critical maternal hormone. In mice, oxytocin enables neuroplasticity in the auditory cortex for maternal recognition of pup distress¹⁵. However, it is unclear how initial parental experience promotes hypothalamic signalling and cortical plasticity for reliable maternal care. Here we continuously monitored the behaviour of female virgin mice co-housed with an experienced mother and litter. This documentary approach was synchronized with neural recordings from the virgin PVN, including oxytocin neurons. These cells were activated as virgins were enlisted in maternal care by experienced mothers, who shepherded virgins into the nest and demonstrated pup retrieval. Virgins visually observed maternal retrieval, which activated PVN oxytocin neurons and promoted alloparenting. Thus rodents can acquire maternal behaviour by social transmission, providing a mechanism for adapting the brains of adult caregivers to infant needs via endogenous oxytocin.

Oxytocin regulates parturition, lactation, parental nurturing, and many other social behaviors in both sexes. The circuit mechanisms by which oxytocin modulates social behavior are receiving increasing attention. Here, we review recent studies on oxytocin modulation of neural circuit function and social behavior, largely enabled by new methods of monitoring and manipulating oxytocin or oxytocin receptor neurons in vivo. These studies indicate that oxytocin can enhance the salience of social stimuli and increase signal-to-noise ratios by modulating spiking and synaptic plasticity in the context of circuits and networks. We highlight oxytocin effects on social behavior in nontraditional organisms such as prairie voles and discuss opportunities to enhance the utility of these organisms for studying circuit-level modulation of social behaviors. We then discuss recent insights into oxytocin neuron activity during social interactions. We conclude by discussing some of the major questions and opportunities in the field ahead.

Vagus nerve stimulation (VNS) suppresses inflammation and autoimmune diseases in preclinical and clinical studies. The underlying molecular, neurological, and anatomical mechanisms have been well characterized using acute electrophysiological stimulation of the vagus. However, there are several unanswered mechanistic questions about the effects of chronic VNS, which require solving numerous technical challenges for a long-term interface with the vagus in mice. Here, we describe a scalable model for long-term VNS in mice developed and validated in 4 research laboratories. We observed significant heart rate responses for at least 4 weeks in 60-90% of animals. Device implantation did not impair vagus-mediated reflexes. VNS using this implant significantly suppressed TNF levels in endotoxemia. Histological examination of implanted nerves revealed fibrotic encapsulation without axonal pathology. This model may be useful to study the physiology of the vagus and provides a tool to systematically investigate long-term VNS as therapy for chronic diseases modeled in mice.

Integration of social cues to initiate adaptive emotional and behavioral responses is a fundamental aspect of animal and human behavior. In humans, social communication includes prominent nonverbal components, such as social touch, gestures and facial expressions. Comparative studies investigating the neural basis of social communication in rodents has historically been centered on olfactory signals and vocalizations, with relatively less focus on non-verbal social cues. Here, we outline two exciting research directions: First, we will review recent observations pointing to a role of social facial expressions in rodents. Second, we will review observations that point to a role of 'non-canonical' rodent body language: body posture signals beyond stereotyped displays in aggressive and sexual behavior. In both sections, we will outline how social neuroscience can build on recent advances in machine learning, robotics and micro-engineering to push these research directions forward towards a holistic systems neurobiology of rodent body language.

Infant cries evoke powerful responses in parents^1-4. Whether parental animals are intrinsically sensitive to neonatal vocalizations, or instead learn about vocal cues for parenting responses is unclear. In mice, pup-naive virgin females do not recognize the meaning of pup distress calls, but retrieve isolated pups to the nest after having been co-housed with a mother and litter^5-9. Distress calls are variable, and require co-caring virgin mice to generalize across calls for reliable retrieval^10,11. Here we show that the onset of maternal behaviour in mice results from interactions between intrinsic mechanisms and experience-dependent plasticity in the auditory cortex. In maternal females, calls with inter-syllable intervals (ISIs) from 75 to 375 milliseconds elicited pup retrieval, and cortical responses were generalized across these ISIs. By contrast, naive virgins were neuronally and behaviourally sensitized to the most common ('prototypical') ISIs. Inhibitory and excitatory neural responses were initially mismatched in the cortex of naive mice, with untuned inhibition and overly narrow excitation. During co-housing experiments, excitatory responses broadened to represent a wider range of ISIs, whereas inhibitory tuning sharpened to form a perceptual boundary. We presented synthetic calls during co-housing and observed that neurobehavioural responses adjusted to match these statistics, a process that required cortical activity and the hypothalamic oxytocin system. Neuroplastic mechanisms therefore build on an intrinsic sensitivity in the mouse auditory cortex, and enable rapid plasticity for reliable parenting behaviour.

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.