Faculty Bibliography

Brain-derived Neurotrophic Factor (BDNF) binds to the TrkB tyrosine kinase receptor, which dictates the sensitivity of neurons to BDNF. A unique feature of TrkB is the ability to be activated by small molecules in a process called transactivation. Here we report that the brain neuropeptide oxytocin increases BDNF TrkB activity in primary cortical neurons and in the mammalian neocortex during postnatal development. Oxytocin produces its effects through a G protein-coupled receptor (GPCR), however, the receptor signaling events that account for its actions have not been fully defined. We find oxytocin rapidly transactivates TrkB receptors in bath application of acute brain slices of 2-week-old mice and in primary cortical culture by increasing TrkB receptor tyrosine phosphorylation. The effects of oxytocin signaling could be distinguished from the related vasopressin receptor. The transactivation of TrkB receptors by oxytocin enhances the clustering of gephyrin, a scaffold protein responsible to coordinate inhibitory responses. Because oxytocin displays pro-social functions in maternal care, cognition, and social attachment, it is currently a focus of therapeutic strategies in autism spectrum disorders. Interestingly, oxytocin and BDNF are both implicated in the pathophysiology of depression, schizophrenia, anxiety, and cognition. These results imply that oxytocin may rely upon crosstalk with BDNF signaling to facilitate its actions through receptor transactivation.

Social interaction deficits seen in psychiatric disorders emerge in early-life and are most closely linked to aberrant neural circuit function. Due to technical limitations, we have limited understanding of how typical versus pathological social behavior circuits develop. Using a suite of invasive procedures in awake, behaving infant rats, including optogenetics, microdialysis, and microinfusions, we dissected the circuits controlling the gradual increase in social behavior deficits following two complementary procedures-naturalistic harsh maternal care and repeated shock alone or with an anesthetized mother. Whether the mother was the source of the adversity (naturalistic Scarcity-Adversity) or merely present during the adversity (repeated shock with mom), both conditions elevated basolateral amygdala (BLA) dopamine, which was necessary and sufficient in initiating social behavior pathology. This did not occur when pups experienced adversity alone. These data highlight the unique impact of social adversity as causal in producing mesolimbic dopamine circuit dysfunction and aberrant social behavior.

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.

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