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Heterosynaptic Plasticity Determines the Set Point for Cortical Excitatory-Inhibitory Balance

Field, Rachel E; D'amour, James A; Tremblay, Robin; Miehl, Christoph; Rudy, Bernardo; Gjorgjieva, Julijana; Froemke, Robert C
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.
PMID: 32213321
ISSN: 1097-4199
CID: 4358042

Locus coeruleus activity improves cochlear implant performance

Glennon, Erin; Valtcheva, Silvana; Zhu, Angela; Wadghiri, Youssef Z; Svirsky, Mario A; Froemke, Robert C
Cochlear implants (CIs) are neuroprosthetic devices that can provide hearing to deaf people1. Despite the benefits offered by CIs, the time taken for hearing to be restored and perceptual accuracy after long-term CI use remain highly variable2,3. CI use is believed to require neuroplasticity in the central auditory system, and differential engagement of neuroplastic mechanisms might contribute to the variability in outcomes4-7. Despite extensive studies on how CIs activate the auditory system4,8-12, the understanding of CI-related neuroplasticity remains limited. One potent factor enabling plasticity is the neuromodulator noradrenaline from the brainstem locus coeruleus (LC). Here we examine behavioural responses and neural activity in LC and auditory cortex of deafened rats fitted with multi-channel CIs. The rats were trained on a reward-based auditory task, and showed considerable individual differences of learning rates and maximum performance. LC photometry predicted when CI subjects began responding to sounds and longer-term perceptual accuracy. Optogenetic LC stimulation produced faster learning and higher long-term accuracy. Auditory cortical responses to CI stimulation reflected behavioural performance, with enhanced responses to rewarded stimuli and decreased distinction between unrewarded stimuli. Adequate engagement of central neuromodulatory systems is thus a potential clinically relevant target for optimizing neuroprosthetic device use.
PMID: 36544024
ISSN: 1476-4687
CID: 5395022

Music Upper Limb Therapy-Integrated (MULT-I) Provides a Feasible Enriched Environment and Reduces Post Stroke Depression: A Pilot Randomized Controlled Trial

Palumbo, Anna; Aluru, Viswanath; Battaglia, Jessica; Geller, Daniel; Turry, Alan; Ross, Marc; Cristian, Adrian; Balagula, Caitlin; Ogedegbe, Gbenga; Khatri, Latika; Chao, Moses V; Froemke, Robert C; Urbanek, Jacek K; Raghavan, Preeti
OBJECTIVE:This study aims to refine Music Upper Limb Therapy - Integrated (MULT-I) to create a feasible enriched environment for stroke rehabilitation and compare its biological and behavioral effects to that of a home exercise program (HEP). DESIGN/METHODS:Randomized mixed-methods study of 30 adults with post-stroke hemiparesis. Serum brain derived neurotrophic factor (BDNF) and oxytocin levels measured biologic effects, and upper limb function, disability, quality of life and emotional well-being were assessed as behavioral outcomes. Participant experiences were explored using semi-structured interviews. RESULTS:MULT-I participants showed reduced depression from pre- to post- intervention as compared to HEP participants. BDNF levels significantly increased for MULT-I participants, but decreased for HEP participants, with a significant difference between groups after excluding those with post-stroke depression. MULT-I participants additionally improved quality of life and self-perceived physical strength, mobility, activity, participation, and recovery from pre- to post-intervention. HEP participants improved upper limb function. Qualitatively, MULT-I provided psychosocial support and enjoyment while HEP supported self-management of rehabilitation. CONCLUSIONS:Implementation of a music enriched environment is feasible, reduces post-stroke depression, and may enhance the neural environment for recovery via increases in BDNF levels. Self-management of rehabilitation through a home exercise program may further improve upper limb function.
PMID: 34864768
ISSN: 1537-7385
CID: 5080352

Automatic mapping of multiplexed social receptive fields by deep learning and GPU-accelerated 3D videography

Ebbesen, Christian L; Froemke, Robert C
Social interactions powerfully impact the brain and the body, but high-resolution descriptions of these important physical interactions and their neural correlates are lacking. Currently, most studies rely on labor-intensive methods such as manual annotation. Scalable and objective tracking methods are required to understand the neural circuits underlying social behavior. Here we describe a hardware/software system and analysis pipeline that combines 3D videography, deep learning, physical modeling, and GPU-accelerated robust optimization, with automatic analysis of neuronal receptive fields recorded in interacting mice. Our system ("3DDD Social Mouse Tracker") is capable of fully automatic multi-animal tracking with minimal errors (including in complete darkness) during complex, spontaneous social encounters, together with simultaneous electrophysiological recordings. We capture posture dynamics of multiple unmarked mice with high spatiotemporal precision (~2 mm, 60 frames/s). A statistical model that relates 3D behavior and neural activity reveals multiplexed 'social receptive fields' of neurons in barrel cortex. Our approach could be broadly useful for neurobehavioral studies of multiple animals interacting in complex low-light environments.
PMID: 35105858
ISSN: 2041-1723
CID: 5153562

Transactivation of TrkB Receptors by Oxytocin and Its G Protein-Coupled Receptor

Mitre, Mariela; Saadipour, Khalil; Williams, Kevin; Khatri, Latika; Froemke, Robert C; Chao, Moses V
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.
PMID: 35721318
ISSN: 1662-5099
CID: 5281802

Bidirectional control of infant rat social behavior via dopaminergic innervation of the basolateral amygdala

Opendak, Maya; Raineki, Charlis; Perry, Rosemarie E; Rincón-Cortés, Millie; Song, Soomin C; Zanca, Roseanna M; Wood, Emma; Packard, Katherine; Hu, Shannon; Woo, Joyce; Martinez, Krissian; Vinod, K Yaragudri; Brown, Russell W; Deehan, Gerald A; Froemke, Robert C; Serrano, Peter A; Wilson, Donald A; Sullivan, Regina M
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.
PMID: 34706218
ISSN: 1097-4199
CID: 5033412

Dementia-linked TDP-43 dysregulation in astrocytes impairs memory, antiviral signaling, and chemokine-mediated astrocytic-neuronal interactions

Murava, Avital Licht; Meadows, Samantha; Palaguachi, Fernando; Song, Soomin C; Bram, Yaron; Zhou, Constance; Schwartz, Robert E; Froemke, Robert C; Orr, Adam L; Orr, Anna G
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.
PMID: 34971156
ISSN: 1552-5279
CID: 5108322

Oxytocin neurons enable social transmission of maternal behaviour

Carcea, Ioana; Caraballo, Naomi López; Marlin, Bianca J; Ooyama, Rumi; Riceberg, Justin S; Mendoza Navarro, Joyce M; Opendak, Maya; Diaz, Veronica E; Schuster, Luisa; Alvarado Torres, Maria I; Lethin, Harper; Ramos, Daniel; Minder, Jessica; Mendoza, Sebastian L; Bair-Marshall, Chloe J; Samadjopoulos, Grace H; Hidema, Shizu; Falkner, Annegret; Lin, Dayu; Mar, Adam; Wadghiri, Youssef Z; Nishimori, Katsuhiko; Kikusui, Takefumi; Mogi, Kazutaka; Sullivan, Regina M; Froemke, Robert C
Maternal care, including by non-biological parents, is important for offspring survival1-8. Oxytocin1,2,9-15, 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.
PMID: 34381215
ISSN: 1476-4687
CID: 4972632

Oxytocin, Neural Plasticity, and Social Behavior

Froemke, Robert C; Young, Larry J
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.
PMID: 33823654
ISSN: 1545-4126
CID: 4976412

Development and characterization of a chronic implant mouse model for vagus nerve stimulation

Mughrabi, Ibrahim T; Hickman, Jordan; Jayaprakash, Naveen; Thompson, Dane; Ahmed, Umair; Papadoyannis, Eleni S; Chang, Yao-Chuan; Abbas, Adam; Datta-Chaudhuri, Timir; Chang, Eric H; Zanos, Theodoros P; Lee, Sunhee C; Froemke, Robert C; Tracey, Kevin J; Welle, Cristin; Al-Abed, Yousef; Zanos, Stavros
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.
PMID: 33821789
ISSN: 2050-084x
CID: 4839132