Olfactory Dysfunction and Balance Dysfunction are Associated with Increased Falls in Older Adults.

OBJECTIVE: This study aims to characterize the association between impairments in olfaction and balance, both of which are mediated in part by the cerebellum, and how this relates to prospective incidence of falls in a cohort of aging adults. METHODS: The Health ABC study was queried to identify 296 participants with data on both olfaction (measured using the 12-item Brief Smell Identification Test) and balance-related function (measured using the Romberg test). The relationship between olfaction and balance was investigated using multivariable logistic regression. Predictors of performance on a standing balance assessment and predictors of falls were studied. RESULTS: Of 296 participants, 52.7% had isolated olfactory dysfunction, 7.4% had isolated balance dysfunction, and 5.7% had dual dysfunction. Severe olfactory dysfunction was associated with increased odds of balance dysfunction when compared to those without olfactory dysfunction, even when adjusting for age, gender, race, education, BMI, smoking, diabetes, depression, and dementia (OR = 4.1, 95% CI [1.5, 13.7], p = 0.011). Dual sensory dysfunction was associated with worse performance on a standing balance assessment (ß = -22.8, 95% CI [-35.6, -10.1], p = 0.0005) and increased falls (ß = 1.5, 95% CI [1.0, 2.3], p = 0.037). CONCLUSION: This study highlights a unique relationship between olfaction and balance, and how dual dysfunction is associated with increased falls. With substantial implications of falls on morbidity and mortality in older adults, this novel relationship between olfaction and balance emphasizes a potentially shared mechanism between olfactory dysfunction and increased fall risk in older adults; however, further study is required to explore the novel relationship of olfaction with balance and future falls. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1964-1969, 2023.

The transcription factor Tbx5 regulates direction-selective retinal ganglion cell development and image stabilization.

The diversity of visual input processed by the mammalian visual system requires the generation of many distinct retinal ganglion cell (RGC) types, each tuned to a particular feature. The molecular code needed to generate this cell-type diversity is poorly understood. Here, we focus on the molecules needed to specify one type of retinal cell: the upward-preferring ON direction-selective ganglion cell (up-oDSGC) of the mouse visual system. Single-cell transcriptomic profiling of up- and down-oDSGCs shows that the transcription factor Tbx5 is selectively expressed in up-oDSGCs. The loss of Tbx5 in up-oDSGCs results in a selective defect in the formation of up-oDSGCs and a corresponding inability to detect vertical motion. A downstream effector of Tbx5, Sfrp1, is also critical for vertical motion detection but not up-oDSGC formation. These results advance our understanding of the molecular mechanisms that specify a rare retinal cell type and show how disrupting this specification leads to a corresponding defect in neural circuitry and behavior.

Purkinje Cell-Specific Knockout of Tyrosine Hydroxylase Impairs Cognitive Behaviors.

Tyrosine hydroxylase (Th) expression has previously been reported in Purkinje cells (PCs) of rodents and humans, but its role in the regulation of behavior is not understood. Catecholamines are well known for facilitating cognitive behaviors and are expressed in many regions of the brain. Here, we investigated a possible role in cognitive behaviors of PC catecholamines, by mapping and testing functional roles of Th positive PCs in mice. Comprehensive mapping analyses revealed a distinct population of Th expressing PCs primarily in the posterior and lateral regions of the cerebellum (comprising about 18% of all PCs). To identify the role of PC catecholamines, we selectively knocked out Th in PCs using a conditional knockout approach, by crossing a Purkinje cell-selective Cre recombinase line, Pcp2-Cre, with a floxed tyrosine hydroxylase mouse line (Thlox/lox) to produce Pcp2-Cre;Thlox/lox mice. This manipulation resulted in approximately 50% reduction of Th protein expression in the cerebellar cortex and lateral cerebellar nucleus, but no reduction of Th in the locus coeruleus, which is known to innervate the cerebellum in mice. Pcp2-Cre;Thlox/lox mice showed impairments in behavioral flexibility, response inhibition, social recognition memory, and associative fear learning relative to littermate controls, but no deficits in gross motor, sensory, instrumental learning, or sensorimotor gating functions. Catecholamines derived from specific populations of PCs appear to support cognitive functions, and their spatial distribution in the cerebellum suggests that they may underlie patterns of activation seen in human studies on the cerebellar role in cognitive function.

Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits.

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.

Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis.

The cerebellar vermis, long associated with axial motor control, has been implicated in a surprising range of neuropsychiatric disorders and cognitive and affective functions. Remarkably little is known, however, about the specific cell types and neural circuits responsible for these diverse functions. Here, using single-cell gene expression profiling and anatomical circuit analyses of vermis output neurons in the mouse fastigial (medial cerebellar) nucleus, we identify five major classes of glutamatergic projection neurons distinguished by gene expression, morphology, distribution, and input-output connectivity. Each fastigial cell type is connected with a specific set of Purkinje cells and inferior olive neurons and in turn innervates a distinct collection of downstream targets. Transsynaptic tracing indicates extensive disynaptic links with cognitive, affective, and motor forebrain circuits. These results indicate that diverse cerebellar vermis functions could be mediated by modular synaptic connections of distinct fastigial cell types with posturomotor, oromotor, positional-autonomic, orienting, and vigilance circuits.

Graded Coexpression of Ion Channel, Neurofilament, and Synaptic Genes in Fast-Spiking Vestibular Nucleus Neurons.

Computations that require speed and temporal precision are implemented throughout the nervous system by neurons capable of firing at very high rates, rapidly encoding and transmitting a rich amount of information, but with substantial metabolic and physical costs. For economical fast spiking and high throughput information processing, neurons need to optimize multiple biophysical properties in parallel, but the mechanisms of this coordination remain unknown. We hypothesized that coordinated gene expression may underlie the coordinated tuning of the biophysical properties required for rapid firing and signal transmission. Taking advantage of the diversity of fast-spiking cell types in the medial vestibular nucleus of mice of both sexes, we examined the relationship between gene expression, ionic currents, and neuronal firing capacity. Across excitatory and inhibitory cell types, genes encoding voltage-gated ion channels responsible for depolarizing and repolarizing the action potential were tightly coexpressed, and their absolute expression levels increased with maximal firing rate. Remarkably, this coordinated gene expression extended to neurofilaments and specific presynaptic molecules, providing a mechanism for coregulating axon caliber and transmitter release to match firing capacity. These findings suggest the presence of a module of genes, which is coexpressed in a graded manner and jointly tunes multiple biophysical properties for economical differentiation of firing capacity. The graded tuning of fast-spiking capacity by the absolute expression levels of specific ion channels provides a counterexample to the widely held assumption that cell-type-specific firing patterns can be achieved via a vast combination of different ion channels.SIGNIFICANCE STATEMENT Although essential roles of fast-spiking neurons in various neural circuits have been widely recognized, it remains unclear how neurons efficiently coordinate the multiple biophysical properties required to maintain high rates of action potential firing and transmitter release. Taking advantage of diverse fast-firing capacities among medial vestibular nucleus neurons of mice, we identify a group of ion channel, synaptic, and structural genes that exhibit mutually correlated expression levels, which covary with firing capacity. Coexpression of this fast-spiking gene module may be a basic strategy for neurons to efficiently and coordinately tune the speed of action potential generation and propagation and transmitter release at presynaptic terminals.

Optogenetically transduced human ES cell-derived neural progenitors and their neuronal progenies: Phenotypic characterization and responses to optical stimulation.

Optogenetically engineered human neural progenitors (hNPs) are viewed as promising tools in regenerative neuroscience because they allow the testing of the ability of hNPs to integrate within nervous system of an appropriate host not only structurally, but also functionally based on the responses of their differentiated progenies to light. Here, we transduced H9 embryonic stem cell-derived hNPs with a lentivirus harboring human channelrhodopsin (hChR2) and differentiated them into a forebrain lineage. We extensively characterized the fate and optogenetic functionality of hChR2-hNPs in vitro with electrophysiology and immunocytochemistry. We also explored whether the in vivo phenotype of ChR2-hNPs conforms to in vitro observations by grafting them into the frontal neocortex of rodents and analyzing their survival and neuronal differentiation. Human ChR2-hNPs acquired neuronal phenotypes (TUJ1, MAP2, SMI-312, and synapsin 1 immunoreactivity) in vitro after an average of 70 days of coculturing with CD1 astrocytes and progressively displayed both inhibitory and excitatory neurotransmitter signatures by immunocytochemistry and whole-cell patch clamp recording. Three months after transplantation into motor cortex of naïve or injured mice, 60-70% of hChR2-hNPs at the transplantation site expressed TUJ1 and had neuronal cytologies, whereas 60% of cells also expressed ChR2. Transplant-derived neurons extended axons through major commissural and descending tracts and issued synaptophysin+ terminals in the claustrum, endopiriform area, and corresponding insular and piriform cortices. There was no apparent difference in engraftment, differentiation, or connectivity patterns between injured and sham subjects. Same trends were observed in a second rodent host, i.e. rat, where we employed longer survival times and found that the majority of grafted hChR2-hNPs differentiated into GABAergic neurons that established dense terminal fields and innervated mostly dendritic profiles in host cortical neurons. In physiological experiments, human ChR2+ neurons in culture generated spontaneous action potentials (APs) 100-170 days into differentiation and their firing activity was consistently driven by optical stimulation. Stimulation generated glutamatergic and GABAergic postsynaptic activity in neighboring ChR2- cells, evidence that hChR2-hNP-derived neurons had established functional synaptic connections with other neurons in culture. Light stimulation of hChR2-hNP transplants in vivo generated complicated results, in part because of the variable response of the transplants themselves. Our findings show that we can successfully derive hNPs with optogenetic properties that are fully transferrable to their differentiated neuronal progenies. We also show that these progenies have substantial neurotransmitter plasticity in vitro, whereas in vivo they mostly differentiate into inhibitory GABAergic neurons. Furthermore, neurons derived from hNPs have the capacity of establishing functional synapses with postsynaptic neurons in vitro, but this outcome is technically challenging to explore in vivo. We propose that optogenetically endowed hNPs hold great promise as tools to explore de novo circuit formation in the brain and, in the future, perhaps launch a new generation of neuromodulatory therapies.

Conversion of upbeat to downbeat nystagmus in Wernicke encephalopathy.

OBJECTIVE: To explain (1) why an initial upbeat nystagmus (UBN) converts to a permanent downbeat nystagmus (DBN) in Wernicke encephalopathy (WE) and (2) why convergence and certain vestibular provocative maneuvers may transiently switch UBN to DBN. METHODS: Following a literature review and study of our 2 patients, we develop hypotheses for the unusual patterns of vertical nystagmus in WE. RESULTS: Our overarching hypothesis is that there is a selective vulnerability and a selective recovery from thiamine deficiency of neurons within brainstem gaze-holding networks. Furthermore, since the circuits affected in WE are commonly paraventricular, especially medially, just under the floor of the fourth ventricle where lie structures important for control of vertical gaze, we suggest the patterns of involvement in WE also reflect a breakdown in vulnerable areas of the blood-brain barrier. Many of the initial deficits of our patients improved over time, but their DBN did not. Irreversible changes in paramedian tract neurons, which project to the cerebellar flocculus, may be the cause. Here we suggest that conversion of UBN to permanent DBN points to thiamine deficiency and may argue for a chronic, nonprogressive DBN/truncal ataxia syndrome. Finally, we posit that the transient switch of UBN to DBN reflects abnormal processing of otolith information about linear acceleration, and often points to a diagnosis of WE. CONCLUSION: Recognizing the unusual patterns of transient switching and then permanent conversion of UBN to DBN in WE is vital since long-term disability from WE may be prevented by timely, parenteral high-dose thiamine.

BK Channels Are Required for Multisensory Plasticity in the Oculomotor System.

Neural circuits are endowed with several forms of intrinsic and synaptic plasticity that could contribute to adaptive changes in behavior, but circuit complexities have hindered linking specific cellular mechanisms with their behavioral consequences. Eye movements generated by simple brainstem circuits provide a means for relating cellular plasticity to behavioral gain control. Here we show that firing rate potentiation, a form of intrinsic plasticity mediated by reductions in BK-type calcium-activated potassium currents in spontaneously firing neurons, is engaged during optokinetic reflex compensation for inner ear dysfunction. Vestibular loss triggers transient increases in postsynaptic excitability, occlusion of firing rate potentiation, and reductions in BK currents in vestibular nucleus neurons. Concurrently, adaptive increases in visually evoked eye movements rapidly restore oculomotor function in wild-type mice but are profoundly impaired in BK channel-null mice. Activity-dependent regulation of intrinsic excitability may be a general mechanism for adaptive control of behavioral output in multisensory circuits.

The astrocytic transporter SLC7A10 (Asc-1) mediates glycinergic inhibition of spinal cord motor neurons.

SLC7A10 (Asc-1) is a sodium-independent amino acid transporter known to facilitate transport of a number of amino acids including glycine, L-serine, L-alanine, and L-cysteine, as well as their D-enantiomers. It has been described as a neuronal transporter with a primary role related to modulation of excitatory glutamatergic neurotransmission. We find that SLC7A10 is substantially enriched in a subset of astrocytes of the caudal brain and spinal cord in a distribution corresponding with high densities of glycinergic inhibitory synapses. Accordingly, we find that spinal cord glycine levels are significantly reduced in Slc7a10-null mice and spontaneous glycinergic postsynaptic currents in motor neurons show substantially diminished amplitudes, demonstrating an essential role for SLC7A10 in glycinergic inhibitory function in the central nervous system. These observations establish the etiology of sustained myoclonus (sudden involuntary muscle movements) and early postnatal lethality characteristic of Slc7a10-null mice, and implicate SLC7A10 as a candidate gene and auto-antibody target in human hyperekplexia and stiff person syndrome, respectively.

Nucleus prepositus hypoglossi lesions produce a unique ocular motor syndrome.

OBJECTIVE: To describe the ocular motor abnormalities in 9 patients with a lesion involving the nucleus prepositus hypoglossi (NPH), a key constituent of a vestibular-cerebellar-brainstem neural network that ensures that the eyes are held steady in all positions of gaze. METHODS: We recorded eye movements, including the vestibulo-ocular reflex during head impulses, in patients with vertigo and a lesion involving the NPH. RESULTS: Our patients showed an ipsilesional-beating spontaneous nystagmus, horizontal gaze-evoked nystagmus more intense on looking toward the ipsilesional side, impaired pursuit more to the ipsilesional side, central patterns of head-shaking nystagmus, contralateral eye deviation, and decreased vestibulo-ocular reflex gain during contralesionally directed head impulses. CONCLUSIONS: We attribute these findings to an imbalance in the NPH-inferior olive-flocculus-vestibular nucleus loop, and the ocular motor abnormalities provide a new brainstem localization for patients with acute vertigo.

Impaired Vestibular Function and Low Bone Mineral Density: Data from the Baltimore Longitudinal Study of Aging.

Animal studies have demonstrated that experimentally induced vestibular ablation leads to a decrease in bone mineral density, through mechanisms mediated by the sympathetic nervous system. Loss of bone mineral density is a common and potentially morbid condition that occurs with aging, and we sought to investigate whether vestibular loss is associated with low bone mineral density in older adults. We evaluated this question in a cross-sectional analysis of data from the Baltimore Longitudinal Study of Aging (BLSA), a large, prospective cohort study managed by the National Institute on Aging (N = 389). Vestibular function was assessed with cervical vestibular evoked myogenic potentials (cVEMPs), a measure of saccular function. Bone mineral density was assessed using dual-energy X-ray absorptiometry (DEXA). In two-way t test analysis, we observed that individuals with reduced vestibular physiologic function had significantly lower bone mineral density. In adjusted multivariate linear regression analyses, we observed that older individuals with reduced vestibular physiologic function had significantly lower bone mineral density, specifically in weight-bearing hip and lower extremity bones. These results suggest that the vestibular system may contribute to bone homeostasis in older adults, notably of the weight-bearing hip bones at greatest risk of osteoporotic fracture. Further longitudinal analysis of vestibular function and bone mineral density in humans is needed to characterize this relationship and investigate the potential confounding effect of physical activity.

Adaptive Acceleration of Visually Evoked Smooth Eye Movements in Mice.

UNLABELLED: The optokinetic response (OKR) consists of smooth eye movements following global motion of the visual surround, which suppress image slip on the retina for visual acuity. The effective performance of the OKR is limited to rather slow and low-frequency visual stimuli, although it can be adaptably improved by cerebellum-dependent mechanisms. To better understand circuit mechanisms constraining OKR performance, we monitored how distinct kinematic features of the OKR change over the course of OKR adaptation, and found that eye acceleration at stimulus onset primarily limited OKR performance but could be dramatically potentiated by visual experience. Eye acceleration in the temporal-to-nasal direction depended more on the ipsilateral floccular complex of the cerebellum than did that in the nasal-to-temporal direction. Gaze-holding following the OKR was also modified in parallel with eye-acceleration potentiation. Optogenetic manipulation revealed that synchronous excitation and inhibition of floccular complex Purkinje cells could effectively accelerate eye movements in the nasotemporal and temporonasal directions, respectively. These results collectively delineate multiple motor pathways subserving distinct aspects of the OKR in mice and constrain hypotheses regarding cellular mechanisms of the cerebellum-dependent tuning of movement acceleration. SIGNIFICANCE STATEMENT: Although visually evoked smooth eye movements, known as the optokinetic response (OKR), have been studied in various species for decades, circuit mechanisms of oculomotor control and adaptation remain elusive. In the present study, we assessed kinematics of the mouse OKR through the course of adaptation training. Our analyses revealed that eye acceleration at visual-stimulus onset primarily limited working velocity and frequency range of the OKR, yet could be dramatically potentiated during OKR adaptation. Potentiation of eye acceleration exhibited different properties between the nasotemporal and temporonasal OKRs, indicating distinct visuomotor circuits underlying the two. Lesions and optogenetic manipulation of the cerebellum provide constraints on neural circuits mediating visually driven eye acceleration and its adaptation.

Vestibular vertigo and comorbid cognitive and psychiatric impairment: the 2008 National Health Interview Survey.

BACKGROUND/AIMS: Patients with vestibular disease have been observed to have concomitant cognitive and psychiatric dysfunction. We evaluated the association between vestibular vertigo, cognitive impairment and psychiatric conditions in a nationally representative sample of US adults. METHODS: We performed a cross-sectional analysis using the 2008 National Health Interview Survey (NHIS), which included a Balance and Dizziness Supplement, and questions about cognitive function and psychiatric comorbidity. We evaluated the association between vestibular vertigo, cognitive impairment (memory loss, difficulty concentrating, confusion) and psychiatric diagnoses (depression, anxiety and panic disorder). RESULTS: We observed an 8.4% 1-year prevalence of vestibular vertigo among US adults. In adjusted analyses, individuals with vestibular vertigo had an eightfold increased odds of 'serious difficulty concentrating or remembering' (OR 8.3, 95% CI 4.8 to 14.6) and a fourfold increased odds of activity limitation due to difficulty remembering or confusion (OR 3.9, 95% CI 3.1 to 5.0) relative to the rest of the US adults. Individuals with vestibular vertigo also had a threefold increased odds of depression (OR 3.4, 95% CI 2.9 to 3.9), anxiety (OR 3.2, 95% CI 2.8 to 3.6) and panic disorder (OR 3.4, 95% CI 2.9 to 4.0). CONCLUSIONS: Our findings indicate that vestibular impairment is associated with increased risk of cognitive and psychiatric comorbidity. The vestibular system is anatomically connected with widespread regions of the cerebral cortex, hippocampus and amygdala. Loss of vestibular inputs may lead to impairment of these cognitive and affective circuits. Further longitudinal research is required to determine if these associations are causal.

Association Between Vestibular and Cognitive Function in U.S. Adults: Data From the National Health and Nutrition Examination Survey.

BACKGROUND: Vestibular function declines with age, and emerging evidence suggests that vestibular loss is associated with cognitive impairment. Whether vestibular dysfunction is associated with age-related cognitive decline is unknown. METHODS: We used data from the 1999-2002 National Health and Nutrition Examination Surveys to evaluate the influence of vestibular function on cognitive performance in a nationally representative sample of U.S. adults aged ≥60 years (n = 1,303). Vestibular function was measured with the modified Romberg test, and cognitive function was measured by the digit symbol substitution (DSS) score test. We also developed structural equation models (SEMs) to explore whether vestibular dysfunction and associated cognitive impairment mediate the effect of age on falls and activities of daily living (ADL) difficulty. RESULTS: Vestibular dysfunction was present in 58% of the study population. In multivariate analyses, vestibular dysfunction was associated with a 3.4-point lower DSS score (95% confidence interval: -5.2, -1.6; p < .0001), equivalent to the effect of 5 years of age. Vestibular dysfunction was also associated with a significantly higher odds of ADL difficulty (p = .001), and with a 2.6-fold increase in the odds of falling (p = .017). SEMs suggested that vestibular function mediates 14.3% of the effect of age on cognitive performance. Further SEMs suggested that lower cognitive performance mediates the association between vestibular loss and ADL difficulty as well as falls. CONCLUSIONS: This study suggests that vestibular dysfunction partially mediates the association between age and cognitive impairment. Moreover, the cognitive impairment that results from vestibular loss may contribute to ADL difficulty and falls in older individuals.

Implementation of linear sensory signaling via multiple coordinated mechanisms at central vestibular nerve synapses.

Signal transfer in neural circuits is dynamically modified by the recent history of neuronal activity. Short-term plasticity endows synapses with nonlinear transmission properties, yet synapses in sensory and motor circuits are capable of signaling linearly over a wide range of presynaptic firing rates. How do such synapses achieve rate-invariant transmission despite history-dependent nonlinearities? Here, ultrastructural, biophysical, and computational analyses demonstrate that concerted molecular, anatomical, and physiological refinements are required for central vestibular nerve synapses to linearly transmit rate-coded sensory signals. Vestibular synapses operate in a physiological regime of steady-state depression imposed by tonic firing. Rate-invariant transmission relies on brief presynaptic action potentials that delimit calcium influx, large pools of rapidly mobilized vesicles, multiple low-probability release sites, robust postsynaptic receptor sensitivity, and efficient transmitter clearance. Broadband linear synaptic filtering of head motion signals is thus achieved by coordinately tuned synaptic machinery that maintains physiological operation within inherent cell biological limitations.

Neuronal classification and marker gene identification via single-cell expression profiling of brainstem vestibular neurons subserving cerebellar learning.

Identification of marker genes expressed in specific cell types is essential for the genetic dissection of neural circuits. Here we report a new strategy for classifying heterogeneous populations of neurons into functionally distinct types and for identifying associated marker genes. Quantitative single-cell expression profiling of genes related to neurotransmitters and ion channels enables functional classification of neurons; transcript profiles for marker gene candidates identify molecular handles for manipulating each cell type. We apply this strategy to the mouse medial vestibular nucleus (MVN), which comprises several types of neurons subserving cerebellar-dependent learning in the vestibulo-ocular reflex. Ion channel gene expression differed both qualitatively and quantitatively across cell types and could distinguish subtle differences in intrinsic electrophysiology. Single-cell transcript profiling of MVN neurons established six functionally distinct cell types and associated marker genes. This strategy is applicable throughout the nervous system and could facilitate the use of molecular genetic tools to examine the behavioral roles of distinct neuronal populations.

Diverse precerebellar neurons share similar intrinsic excitability.

The cerebellum dedicates a majority of the brain's neurons to processing a wide range of sensory, motor, and cognitive signals. Stereotyped circuitry within the cerebellar cortex suggests that similar computations are performed throughout the cerebellum, but little is known about whether diverse precerebellar neurons are specialized for the nature of the information they convey. In vivo recordings indicate that firing responses to sensory or motor stimuli vary dramatically across different precerebellar nuclei, but whether this reflects diverse synaptic inputs or differentially tuned intrinsic excitability has not been determined. We targeted whole-cell patch-clamp recordings to neurons in eight precerebellar nuclei which were retrogradely labeled from different regions of the cerebellum in mice. Intrinsic physiology was compared across neurons in the medial vestibular, external cuneate, lateral reticular, prepositus hypoglossi, supragenual, Roller/intercalatus, reticularis tegmenti pontis, and pontine nuclei. Within the firing domain, precerebellar neurons were remarkably similar. Firing faithfully followed temporally modulated inputs, could be sustained at high rates, and was a linear function of input current over a wide range of inputs and firing rates. Pharmacological analyses revealed common expression of Kv3 currents, which were essential for a wide linear firing range, and of SK (small-conductance calcium-activated potassium) currents, which were essential for a wide linear input range. In contrast, membrane properties below spike threshold varied considerably within and across precerebellar nuclei, as evidenced by variability in postinhibitory rebound firing. Our findings indicate that diverse precerebellar neurons perform similar scaling computations on their inputs but may be differentially tuned to synaptic inhibition.

Multiple types of cerebellar target neurons and their circuitry in the vestibulo-ocular reflex.

The cerebellum influences behavior and cognition exclusively via Purkinje cell synapses onto neurons in the deep cerebellar and vestibular nuclei. In contrast with the rich information available about the organization of the cerebellar cortex and its synaptic inputs, relatively little is known about microcircuitry postsynaptic to Purkinje cells. Here we examined the cell types and microcircuits through which Purkinje cells influence an oculomotor behavior controlled by the cerebellum, the horizontal vestibulo-ocular reflex, which involves only two eye muscles. Using a combination of anatomical tracing and electrophysiological recordings in transgenic mouse lines, we identified several classes of neurons in the medial vestibular nucleus that receive Purkinje cell synapses from the cerebellar flocculus. Glycinergic and glutamatergic flocculus target neurons (FTNs) with somata densely surrounded by Purkinje cell terminals projected axons to the ipsilateral abducens and oculomotor nuclei, respectively. Of three additional types of FTNs that were sparsely innervated by Purkinje cells, glutamatergic and glycinergic neurons projected to the contralateral and ipsilateral abducens, respectively, and GABAergic neurons projected to contralateral vestibular nuclei. Densely innervated FTNs had high spontaneous firing rates and pronounced postinhibitory rebound firing, and were physiologically homogeneous, whereas the intrinsic excitability of sparsely innervated FTNs varied widely. Heterogeneity in the molecular expression, physiological properties, and postsynaptic targets of FTNs implies that Purkinje cell activity influences the neural control of eye movements in several distinct ways. These results indicate that the cerebellum regulates a simple reflex behavior via at least five different cell types that are postsynaptic to Purkinje cells.