Central Circuits Research Articles

Electronics-free pneumatic circuits for controlling soft-legged robots.

Pneumatically actuated soft robots have recently shown promise for their ability to adapt to their environment. Previously, these robots have been controlled with electromechanical components, such as valves and pumps, that are typically bulky and expensive. Here, we present an approach for controlling the gaits of soft-legged robots using simple pneumatic circuits without any electronic components. This approach produces locomotive gaits using ring oscillators composed of soft valves that generate oscillating signals analogous to biological central pattern generator neural circuits, which are acted upon by pneumatic logic components in response to sensor inputs. Our robot requires only a constant source of pressurized air to power both control and actuation systems. We demonstrate this approach by designing pneumatic control circuits to generate walking gaits for a soft-legged quadruped with three degrees of freedom per leg and to switch between gaits to control the direction of locomotion. In experiments, we controlled a basic walking gait using only three pneumatic memory elements (valves). With two oscillator circuits (seven valves), we were able to improve locomotion speed by 270%. Furthermore, with a pneumatic memory element we designed to mimic a double-pole double-throw switch, we demonstrated a control circuit that allowed the robot to select between gaits for omnidirectional locomotion and to respond to sensor input. This work represents a step toward fully autonomous, electronics-free walking robots for applications including low-cost robotics for entertainment and systems for operation in environments where electronics may not be suitable.

MicroRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity

Adaptive thermogenesis is essential for survival, and therefore is tightly regulated by a central neural circuit. Here, we show that microRNA (miR)-33 in the brain is indispensable for adaptive thermogenesis. Cold stress increases miR-33 levels in the hypothalamus and miR-33−/− mice are unable to maintain body temperature in cold environments due to reduced sympathetic nerve activity and impaired brown adipose tissue (BAT) thermogenesis. Analysis of miR-33f/f dopamine-β-hydroxylase (DBH)-Cre mice indicates the importance of miR-33 in Dbh-positive cells. Mechanistically, miR-33 deficiency upregulates gamma-aminobutyric acid (GABA)A receptor subunit genes such as Gabrb2 and Gabra4. Knock-down of these genes in Dbh-positive neurons rescues the impaired cold-induced thermogenesis in miR-33f/fDBH-Cre mice. Conversely, increased gene dosage of miR-33 in mice enhances thermogenesis. Thus, miR-33 in the brain contributes to maintenance of BAT thermogenesis and whole-body metabolism via enhanced sympathetic nerve tone through suppressing GABAergic inhibitory neurotransmission. This miR-33-mediated neural mechanism may serve as a physiological adaptive defense mechanism for several stresses including cold stress.

Preserved noradrenergic function in Parkinson's disease patients with rest tremor

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PDT+) or without (PDT-) rest tremor had 11C-methylreboxetine(11C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PDT+ compared to PDT-. MethodsSixty-five PD patients and 28 healthy controls (HC) were scanned with 11C-MeNER PET. Patients were categorized as PDT+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PDT-. Simplified reference tissue model 2 distribution volume ratios (DVR) for 11C-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using ‘region’, and ‘group’ as factors and the interaction of ‘region x group’ was examined. ResultsTremor positive PD patients had a significantly higher mean 11C-MeNER DVR compared to PDT- in LC and thalamus. The PDT+ mean LC DVR was similar to that of HC. PDT+ mean 11C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PDT- group showed significantly lower mean 11C-MeNER DVR across all regions compared to HC. ConclusionWhile both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PDT+ in LC and thalamus. The greater loss of noradrenergic transporters in PDT- in LC and thalamus compared with PDT+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype.

Functional disruption of cortical cingulate activity attenuates visceral hypersensitivity and anxiety induced by acute experimental colitis

Visceral pain is a highly complex experience and is the most common pathological feature in patients suffering from inflammatory gastrointestinal disorders. Whilst it is increasingly recognized that aberrant neural processing within the gut-brain axis plays a key role in development of neurological symptoms, the underlying mechanisms remain largely unknown. Here, we investigated the cortical activation patterns and effects of non-invasive chemogenetic suppression of cortical activity on visceral hypersensitivity and anxiety-related phenotypes in a well-characterized mouse model of acute colitis induced by dextran sulfate sodium (DSS). We found that within the widespread cortical network, the mid-cingulate cortex (MCC) was consistently highly activated in response to innocuous and noxious mechanical stimulation of the colon. Furthermore, during acute experimental colitis, impairing the activity of the MCC successfully alleviated visceral hypersensitivity, anxiety-like behaviors and visceromotor responses to colorectal distensions (CRDs) via downregulating the excitability of the posterior insula (PI), somatosensory and the rostral anterior cingulate cortices (rACC), but not the prefrontal or anterior insula cortices. These results provide a mechanistic insight into the central cortical circuits underlying painful visceral manifestations and implicate MCC plasticity as a putative target in cingulate-mediated therapies for bowel disorders.

Sensational developments in somatosensory development?

This is an overview of the most recent advances pertaining to the development of the cardinal components of the somatosensory system: the peripheral sensory neurons that perceive somatosensory stimuli, the first line central nervous system circuits that modulate them, and the higher structures such as the somatosensory cortex that eventually compute a motor response to them. Here, I also review the most recent findings concerning the role of neuronal activity in somatosensory development, formation of somatotopic maps, insights into human somatosensory development and the link between aberrant somatosensation and neurodevelopmental disorders.

Kappa Opioid Receptor Ligands and Pharmacology: Diphenethylamines, a Class of Structurally Distinct, Selective Kappa Opioid Ligands.

The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system. The endogenous kappa opioid system is expressed in the central and peripheral nervous systems, and has a key role in modulating pain in central and peripheral neuronal circuits and a wide array of physiological functions and neuropsychiatric behaviors (e.g., stress, reward, emotion, motivation, cognition, epileptic seizures, itch, and diuresis). We review the latest advances in pharmacology of the KOR, chemical developments on KOR ligands with advances and challenges, and therapeutic and potential applications of KOR ligands. Diverse discovery strategies of KOR ligands targeting natural, naturally derived, and synthetic compounds with different scaffolds, as small molecules or peptides, with short or long-acting pharmacokinetics, and central or peripheral site of action, are discussed. These research efforts led to ligands with distinct pharmacological properties, as agonists, partial agonists, biased agonists, and antagonists. Differential modulation of KOR signaling represents a promising strategy for developing pharmacotherapies for several human diseases, either by activating (treatment of pain, pruritus, and epilepsy) or blocking (treatment of depression, anxiety, and addiction) the receptor. We focus on the recent chemical and pharmacological advances on diphenethylamines, a new class of structurally distinct, selective KOR ligands. Design strategies and investigations to define structure-activity relationships together with in vivo pharmacology of diphenethylamines as agonists, biased agonists, and antagonists and their potential use as therapeutics are discussed.

Central circuit mechanisms of sympathetic and behavioral responses to psychological stress

Central circuit mechanisms of sympathetic and behavioral responses to psychological stress

Whole-brain monosynaptic inputs and outputs of glutamatergic neurons of the vestibular nuclei complex in mice

Vestibular nuclei complex (VN) glutamatergic neurons play a critical role in the multisensory and multimodal processing. The dysfunction of VN leads to a series of vestibular concurrent symptoms, such as disequilibrium, spatial disorientation, autonomic disorders and even emotion disorders. However, the reciprocal neural connectivity in the whole brain of VN glutamatergic neurons was incompletely understood. Here, we employed a cell-type-specific, cre-dependent, modified virus vector to retrogradely and anterogradely trace VN glutamatergic neurons in the VGLUT2-IRES-Cre mouse line. We identified and analyzed statistically the afferents and efferents of VN glutamatergic neurons in the whole brain, and also reconstructed monosynaptic inputs distribution of VN glutamatergic neurons at the three-dimensional level with the combination of a fluorescence micro-optical sectioning tomography system (fMOST). We found that VN glutamatergic neurons primarily received afferents from 57 nuclei and send efferents to 59 nuclei in the whole brain, intensively located in the brainstem and cerebellum. Projections from nuclei in the cerebellum targeting VN glutamatergic neurons mainly performed the balance control – the principal function of the vestibular system. In addition, VN glutamatergic neurons sent projections to oculomotor nucleus, trochlear nucleus and abducens nucleus dominating the eye movement. Except for the maintenance of balance, VN glutamatergic neurons were also directly connected with other functional regions, such as sleep-wake state (locus coeruleus, dorsal raphe nucleus, and laterodorsal tegmental nucleus, gigantocellular reticular nucleus, lateral paragigantocellular nucleus, periaqueductal gray, subcoeruleus nucleus, parvicellular reticular nucleus, paramedian raphe nucleus), and emotional regulation (locus coeruleus and dorsal raphe nucleus). Hence, this study revealed a comprehensive whole-brain neural connectivity of VN glutamatergic neurons and provided with a neuroanatomic foundation to further study on central vestibular circuits.

Why Does the Face Predict the Brain? Neural Crest Induction, Craniofacial Morphogenesis, and Neural Circuit Development

Mesenchephalic and rhombencephalic neural crest cells generate the craniofacial skeleton, special sensory organs, and subsets of cranial sensory receptor neurons. They do so while preserving the anterior-posterior (A-P) identity of their neural tube origins. This organizational principle is paralleled by central nervous system circuits that receive and process information from facial structures whose A-P identity is in register with that in the brain. Prior to morphogenesis of the face and its circuits, however, neural crest cells act as “inductive ambassadors” from distinct regions of the neural tube to induce differentiation of target craniofacial domains and establish an initial interface between the brain and face. At every site of bilateral, non-axial secondary induction, neural crest constitutes all or some of the mesenchymal compartment for non-axial mesenchymal/epithelial (M/E) interactions. Thus, for epithelial domains in the craniofacial primordia, aortic arches, limbs, the spinal cord, and the forebrain (Fb), neural crest-derived mesenchymal cells establish local sources of inductive signaling molecules that drive morphogenesis and cellular differentiation. This common mechanism for building brains, faces, limbs, and hearts, A-P axis specified, neural crest-mediated M/E induction, coordinates differentiation of distal structures, peripheral neurons that provide their sensory or autonomic innervation in some cases, and central neural circuits that regulate their behavioral functions. The essential role of this neural crest-mediated mechanism identifies it as a prime target for pathogenesis in a broad range of neurodevelopmental disorders. Thus, the face and the brain “predict” one another, and this mutual developmental relationship provides a key target for disruption by developmental pathology.

Fruitless mutant male mosquitoes gain attraction to human odor.

The Aedesaegypti mosquito shows extreme sexual dimorphism in feeding. Only females are attracted to and obtain a blood-meal from humans, which they use to stimulate egg production. The fruitless gene is sex-specifically spliced and encodes a BTB zinc-finger transcription factor proposed to be a master regulator of male courtship and mating behavior across insects. We generated fruitless mutant mosquitoes and showed that males failed to mate, confirming the ancestral function of this gene in male sexual behavior. Remarkably, fruitless males also gain strong attraction to a live human host, a behavior that wild-type males never display, suggesting that male mosquitoes possess the central or peripheral neural circuits required to host-seek and that removing fruitless reveals this latent behavior in males. Our results highlight an unexpected repurposing of a master regulator of male-specific sexual behavior to control one module of female-specific blood-feeding behavior in a deadly vector of infectious diseases.

Plastic changes in primate motor cortex following paired peripheral nerve stimulation.

Repeated paired stimulation of two peripheral nerves can produce lasting changes in motor cortical excitability, but little is known of the underlying neuronal basis. Here, we trained two macaque monkeys to perform selective thumb and index finger abduction movements. Neural activity was recorded from the contralateral primary motor cortex during task performance, and following stimulation of the ulnar and median nerves, and the nerve supplying the extensor digitorum communis (EDC) muscle. Responses were compared before and after 1 h of synchronous or asynchronous paired ulnar/median nerve stimulation. Task performance was significantly enhanced after asynchronous and impaired after synchronous stimulation. The amplitude of short latency neural responses to median and ulnar nerve stimulation was increased after asynchronous stimulation; later components were reduced after synchronous stimulation. Synchronous stimulation increased neural activity during thumb movement and decreased it during index finger movement; asynchronous stimulation decreased activity during both movements. To assess how well neural activity could separate behavioral or sensory conditions, linear discriminant analysis was used to decode which nerve was stimulated, or which digit moved. Decoding accuracy for nerve stimulation was decreased after synchronous and increased after asynchronous paired stimulation. Decoding accuracy for task performance was decreased after synchronous but was unchanged after asynchronous paired stimulation. Paired stimulation produces changes in motor cortical circuits that outlast the stimulation. Some of these changes depend on precise stimulus timing.NEW & NOTEWORTHY Paired stimulation of peripheral nerves for 1 h induced lasting changes in neural responses within the motor cortex to nerve stimulation and to performance of a behavioral task. These changes were sufficient to alter the efficiency with which activity could encode stimulus type. Stimuli that can be easily applied noninvasively in human subjects can alter central motor circuits.

Central processing of leg proprioception in Drosophila.

Proprioception, the sense of self-movement and position, is mediated by mechanosensory neurons that detect diverse features of body kinematics. Although proprioceptive feedback is crucial for accurate motor control, little is known about how downstream circuits transform limb sensory information to guide motor output. Here we investigate neural circuits in Drosophila that process proprioceptive information from the fly leg. We identify three cell types from distinct developmental lineages that are positioned to receive input from proprioceptor subtypes encoding tibia position, movement, and vibration. 13Bα neurons encode femur-tibia joint angle and mediate postural changes in tibia position. 9Aα neurons also drive changes in leg posture, but encode a combination of directional movement, high frequency vibration, and joint angle. Activating 10Bα neurons, which encode tibia vibration at specific joint angles, elicits pausing in walking flies. Altogether, our results reveal that central circuits integrate information across proprioceptor subtypes to construct complex sensorimotor representations that mediate diverse behaviors, including reflexive control of limb posture and detection of leg vibration.

Musings on the wanderer: What's new in our understanding of vago-vagal reflexes? VI. Central vagal circuits that control glucose metabolism.

Neurons in the brain stem dorsal vagal complex (DVC) take part in a continuous bidirectional crosstalk, in which they receive and respond to a vast array of signaling molecules, including glucose. Importantly, chronic dysregulation of blood glucose concentration, a hallmark of high prevalence pathologies, such as diabetes and metabolic syndrome, can induce neuroplasticity in DVC neural networks, which is hypothesized to either contribute to or compensate for the glycemic or insulinemic dysregulation observed in these conditions. Here, we revisit the topic of vagal reflexes to review recent research on the importance of DVC function in regulating systemic glucose homeostasis and the neuroplastic changes in this brain region that are associated with systemic glucose alterations. We also discuss the critical connection between these nuclei and the gut and the role of central vagal circuits in the favorable outcomes associated with bariatric surgical procedures for metabolic disorders.

Abnormal morphology and subcortical projections to the medial geniculate in an animal model of autism.

Auditory dysfunction, including hypersensitivity and tinnitus, is a common symptom of autism spectrum disorder (ASD). Prenatal exposure to the antiseizure medication valproic acid (VPA) significantly increases the risk of ASD in humans and similar exposure is utilized as an animal model of ASD in rodents. Animals exposed to VPA in utero have abnormal activity in their auditory cortex in response to sounds, fewer neurons, abnormal neuronal morphology, reduced expression of calcium-binding proteins, and reduced ascending projections to the central nucleus of the inferior colliculus. Unfortunately, these previous studies of central auditory circuits neglect the medial geniculate (MG), which serves as an important auditory relay from the midbrain to the auditory cortex. Here, we examine the structure and connectivity of the medial geniculate (MG) in rats prenatally exposed to VPA. Our results indicate that VPA exposure results in significantly smaller and fewer neurons in the ventral and medial nuclei of the MG. Furthermore, injections of the retrograde tract tracer fluorogold (FG) in the MG result in significantly fewer FG+ neurons in the inferior colliculus, superior olivary complex, and ventral cochlear nucleus. Together, we interpret these findings to indicate that VPA exposure results in hypoplasia throughout the auditory circuits and that VPA has a differential impact on some long-range axonal projections from brainstem centers to the thalamus. Together, our findings support the widespread impact of VPA on neurons and sensory circuits in the developing brain.

A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress-induced bone loss.

Homeostasis of bone metabolism is regulated by the central nervous system, and mood disorders such as anxiety are associated with bone metabolism abnormalities, yet our understanding of the central neural circuits regulating bone metabolism is limited. Here, we demonstrate that chronic stress in crewmembers resulted in decreased bone density and elevated anxiety in an isolated habitat mimicking a space station. We then used a mouse model to demonstrate that GABAergic neural circuitry in the ventromedial hypothalamus (VMH) mediates chronic stress-induced bone loss. We show that GABAergic inputs in the dorsomedial VMH arise from a specific group of somatostatin neurons in the posterior region of the bed nucleus of the stria terminalis, which is indispensable for stress-induced bone loss and is able to trigger bone loss in the absence of stressors. In addition, the sympathetic system and glutamatergic neurons in the nucleus tractus solitarius were employed to regulate stress-induced bone loss. Our study has therefore identified the central neural mechanism by which chronic stress-induced mood disorders, such as anxiety, influence bone metabolism.

FUS-dependent loading of SUV39H1 to OCT4 pseudogene-lncRNA programs a silencing complex with OCT4 promoter specificity

The resurrection of pseudogenes during evolution produced lncRNAs with new biological function. Here we show that pseudogene-evolution created an Oct4 pseudogene lncRNA that is able to direct epigenetic silencing of the parental Oct4 gene via a 2-step, lncRNA dependent mechanism. The murine Oct4 pseudogene 4 (mOct4P4) lncRNA recruits the RNA binding protein FUS to allow the binding of the SUV39H1 HMTase to a defined mOct4P4 lncRNA sequence element. The mOct4P4-FUS-SUV39H1 silencing complex holds target site specificity for the parental Oct4 promoter and interference with individual components results in loss of Oct4 silencing. SUV39H1 and FUS do not bind parental Oct4 mRNA, confirming the acquisition of a new biological function by the mOct4P4 lncRNA. Importantly, all features of mOct4P4 function are recapitulated by the human hOCT4P3 pseudogene lncRNA, indicating evolutionary conservation. Our data highlight the biological relevance of rapidly evolving lncRNAs that infiltrate into central epigenetic regulatory circuits in vertebrate cells.

Descending Modulation of Laryngeal Vagal Sensory Processing in the Brainstem Orchestrated by the Submedius Thalamic Nucleus.

The nodose and jugular vagal ganglia supply sensory innervation to the airways and lungs. Jugular vagal airway sensory neurons wire into a brainstem circuit with ascending projections into the submedius thalamic nucleus (SubM) and ventrolateral orbital cortex (VLO), regions known to regulate the endogenous analgesia system. Here we investigate whether the SubM-VLO circuit exerts descending regulation over airway vagal reflexes in male and female rats using a range of neuroanatomical tracing, reflex physiology, and chemogenetic techniques. Anterograde and retrograde neuroanatomical tracing confirmed the connectivity of the SubM and VLO. Laryngeal stimulation in anesthetized rats reduced respiration, a reflex that was potently inhibited by activation of SubM. Conversely, inhibition of SubM potentiated laryngeal reflex responses, while prior lesions of VLO abolished the effects of SubM stimulation. In conscious rats, selective chemogenetic activation of SubM neurons specifically projecting to VLO significantly inhibited respiratory responses evoked by inhalation of the nociceptor stimulant capsaicin. Jugular vagal inputs to SubM via the medullary paratrigeminal nucleus were confirmed using anterograde transsynaptic conditional herpes viral tracing. Respiratory responses evoked by microinjections of capsaicin into the paratrigeminal nucleus were significantly attenuated by SubM stimulation, whereas those evoked via the nucleus of the solitary tract were unaltered. These data suggest that jugular vagal sensory pathways input to a nociceptive thalamocortical circuit capable of regulating jugular sensory processing in the medulla. This circuit organization suggests an intersection between vagal sensory pathways and the endogenous analgesia system, potentially important for understanding vagal sensory processing in health and mechanisms of hypersensitivity in disease.SIGNIFICANCE STATEMENT Jugular vagal sensory pathways are increasingly recognized for their important role in defensive respiratory responses evoked from the airways. Jugular ganglia neurons wire into a central circuit that is notable for overlapping with somatosensory processing networks in the brain rather than the viscerosensory circuits in receipt of inputs from the nodose vagal ganglia. Here we demonstrate a novel and functionally relevant example of intersection between vagal and somatosensory processing in the brain. The findings of the study offer new insights into interactions between vagal and spinal sensory processing, including the medullary targets of the endogenous analgesia system, and offer new insights into the central processes involved in airway defense in health and disease.

Non-invasive vagus nerve stimulation attenuates proinflammatory cytokines and augments antioxidant levels in the brainstem and forebrain regions\xa0of Dahl salt sensitive rats

The anti-inflammatory effects of vagus nerve stimulation are well known. It has recently been shown that low-level, transcutaneous stimulation of vagus nerve at the tragus (LLTS) reduces cardiac inflammation in a rat model of heart failure with preserved ejection fraction (HFpEF). The mechanisms by which LLTS affect the central neural circuits within the brain regions that are important for the regulation of cardiac vagal tone are not clear. Female Dahl salt-sensitive rats were initially fed with either low salt (LS) or high salt (HS) diet for a period of 6 weeks, followed by sham or active stimulation (LLTS) for 30 min daily for 4 weeks. To study the central effects of LLTS, four brainstem (SP5, NAb, NTS, and RVLM) and two forebrain sites (PVN and SFO) were examined. HS diet significantly increased the gene expression of proinflammatory cytokines in the SP5 and SFO. LLTS reversed HS diet-induced changes at both these sites. Furthermore, LLTS augmented the levels of antioxidant Nrf2 in the SP5 and SFO. Taken together, these findings suggest that LLTS has central anti-inflammatory and antioxidant properties that could mediate the neuromodulation of cardiac vagal tone in the rat model of HFpEF.

Cholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation.

Aging is a complex biological process that increases the risk of age-related cognitive degenerative diseases such as dementia, including Alzheimer’s disease (AD), Lewy Body Dementia (LBD), and mild cognitive impairment (MCI). Even non-pathological aging of the brain can involve chronic oxidative and inflammatory stress, which disrupts the communication and balance between the brain and the immune system. There has been an increasingly strong connection found between chronic neuroinflammation and impaired memory, especially in AD. While microglia and astrocytes, the resident immune cells of the central nervous system (CNS), exerting beneficial effects during the acute inflammatory phase, during chronic neuroinflammation they can become more detrimental. Central cholinergic circuits are involved in maintaining normal cognitive function and regulating signaling within the entire cerebral cortex. While neuronal-glial cholinergic signaling is anti-inflammatory and anti-oxidative, central cholinergic neuronal degeneration is implicated in impaired learning, memory sleep regulation, and attention. Although there is evidence of cholinergic involvement in memory, fewer studies have linked the cholinergic anti-inflammatory and anti-oxidant pathways to memory processes during development, normal aging, and disease states. This review will summarize the current knowledge of cholinergic effects on microglia and astroglia, and their role in both anti-inflammatory and anti-oxidant mechanisms, concerning normal aging and chronic neuroinflammation. We provided details on how stimulation of α7 nicotinic acetylcholine (α7nACh) receptors can be neuroprotective by increasing amyloid-β phagocytosis, decreasing inflammation and reducing oxidative stress by promoting the nuclear factor erythroid 2-related factor 2 (Nrf2) pathways and decreasing the release of pro-inflammatory cytokines. There is also evidence for astroglial α7nACh receptor stimulation mediating anti-inflammatory and antioxidant effects by inhibiting the nuclear factor-κB (NF-κB) pathway and activating the Nrf2 pathway respectively. We conclude that targeting cholinergic glial interactions between neurons and glial cells via α7nACh receptors could regulate neuroinflammation and oxidative stress, relevant to the treatment of several neurodegenerative diseases.

Long-term potentiation of glycinergic synapses by semi-natural stimulation patterns during tonotopic map refinement

Before the onset of hearing, cochlea-generated patterns of spontaneous spike activity drive the maturation of central auditory circuits. In the glycinergic sound localization pathway from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) this spontaneous activity guides the strengthening and silencing of synapses which underlies tonotopic map refinement. However, the mechanisms by which patterned activity regulates synaptic refinement in the MNTB-LSO pathway are still poorly understood. To address this question, we recorded from LSO neurons in slices from prehearing mice while stimulating MNTB afferents with stimulation patterns that mimicked those present in vivo. We found that these semi-natural stimulation patterns reliably elicited a novel form of long-term potentiation (LTP) of MNTB-LSO synapses. Stimulation patterns that lacked the characteristic high-frequency (200 Hz) component of prehearing spike activity failed to elicit potentiation. LTP was calcium dependent, required the activation of both g-protein coupled GABAB and metabotropic glutamate receptors and involved an increase in postsynaptic glycine receptor-mediated currents. Our results provide a possible mechanism linking spontaneous spike bursts to tonotopic map refinement and further highlight the importance of the co-release of GABA and glutamate from immature glycinergic MNTB terminals.