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Abstract Thalamo-cortical networks are central to seizures, yet it is unclear how these circuits initiate seizures. We test whether a facial region of the thalamus, the ventral posteromedial nucleus (VPM), is a source of generalized, convulsive motor seizures and if convergent VPM input drives the behavior. To address this question, we devise an in vivo optogenetic mouse model to elicit convulsive motor seizures by driving these inputs and perform single-unit recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find dynamic activity with biphasic properties, raising the possibility that heterogenous activity promotes seizures. Virus tracing identifies cerebellar and cerebral cortical afferents as robust contributors to the seizures. Of these inputs, only microinfusion of lidocaine into the cerebellar nuclei blocks seizure initiation. Our data reveal the VPM as a source of generalized convulsive seizures, with cerebellar input providing critical signals.

Abstract Insults to the developing cerebellum can cause motor, language, and social deficits. Here, we investigate whether developmental insults to different cerebellar neurons constrain the ability to acquire cerebellar-dependent behaviors. We perturb cerebellar cortical or nuclei neuron function by eliminating glutamatergic neurotransmission during development, and then we measure motor and social behaviors in early postnatal and adult mice. Altering cortical and nuclei neurons impacts postnatal motor control and social vocalizations. Normalizing neurotransmission in cortical neurons but not nuclei neurons restores social behaviors while the motor deficits remain impaired in adults. In contrast, manipulating only a subset of nuclei neurons leaves social behaviors intact but leads to early motor deficits that are restored by adulthood. Our data uncover that glutamatergic neurotransmission from cerebellar cortical and nuclei neurons differentially control the acquisition of motor and social behaviors, and that the brain can compensate for some but not all perturbations to the developing cerebellum.

Dystonia is a highly prevalent movement disorder that can manifest at any time across the lifespan. An increasing number of investigations have tied this disorder to dysfunction of a broad “dystonia network” encompassing the cerebellum, thalamus, basal ganglia, and cortex. However, pinpointing how dysfunction of the various anatomic components of the network produces the wide variety of dystonia presentations across etiologies remains a difficult problem. In this review, a discussion of functional network findings in non-mendelian etiologies of dystonia is undertaken. Initially acquired etiologies of dystonia and how lesion location leads to alterations in network function are explored, first through an examination of cerebral palsy, in which early brain injury may lead to dystonic/dyskinetic forms of the movement disorder. The discussion of acquired etiologies then continues with an evaluation of the literature covering dystonia resulting from focal lesions followed by the isolated focal dystonias, both idiopathic and task dependent. Next, how the dystonia network responds to therapeutic interventions, from the “geste antagoniste” or “sensory trick” to botulinum toxin and deep brain stimulation, is covered with an eye towards finding similarities in network responses with effective treatment. Finally, an examination of how focal network disruptions in mouse models has informed our understanding of the circuits involved in dystonia is provided. Together, this article aims to offer a synthesis of the literature examining dystonia from the perspective of brain networks and it provides grounding for the perspective of dystonia as disorder of network function.

Dystonia is a movement disorder characterized by involuntary co- or over-contractions of the muscles, which results in abnormal postures and movements. These symptoms arise from the pathophysiology of a brain-wide dystonia network. There is mounting evidence suggesting that the cerebellum is a central node in this network. For example, manipulations that target the cerebellum cause dystonic symptoms in mice, and cerebellar neuromodulation reduces these symptoms. Although numerous findings provide insight into dystonia pathophysiology, they also raise further questions. Namely, how does cerebellar pathophysiology cause the diverse motor abnormalities in dystonia, tremor, and ataxia? Here, we describe recent work in rodents showing that distinct cerebellar circuit abnormalities could define different disorders and we discuss potential mechanisms that determine the behavioral presentation of cerebellar diseases.

Although dystonia is the third most common movement disorder, patients often also experience debilitating nonmotor defects including impaired sleep. The cerebellum is a central component of a “dystonia network” that plays various roles in sleep regulation. Importantly, the primary driver of sleep impairments in dystonia remains poorly understood. The cerebellum, along with other nodes in the motor circuit, could disrupt sleep. However, it is unclear how the cerebellum might alter sleep and mobility. To disentangle the impact of cerebellar dysfunction on motion and sleep, we generated two mouse genetic models of dystonia that have overlapping cerebellar circuit miswiring but show differing motor phenotype severity: Ptf1aCre;Vglut2fx/fx and Pdx1Cre;Vglut2fx/fx mice. In both models, excitatory climbing fiber to Purkinje cell neurotransmission is blocked, but only the Ptf1aCre;Vglut2fx/fx mice have severe twisting. Using in vivo ECoG and EMG recordings we found that both mutants spend greater time awake and in NREM sleep at the expense of REM sleep. The increase in awake time is driven by longer awake bouts rather than an increase in bout number. We also found a longer latency to reach REM in both mutants, which is similar to what is reported in human dystonia. We uncovered independent but parallel roles for cerebellar circuit dysfunction and motor defects in promoting sleep quality versus posture impairments in dystonia.

The deep brain stimulation (DBS) Think Tank X was held on August 17–19, 2022 in Orlando FL. The session organizers and moderators were all women with the theme women in neuromodulation. Dr. Helen Mayberg from Mt. Sinai, NY was the keynote speaker. She discussed milestones and her experiences in developing depression DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging DBS technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank X speakers was that DBS has continued to expand in scope however several indications have reached the “trough of disillusionment.” DBS for depression was considered as “re-emerging” and approaching a slope of enlightenment. DBS for depression will soon re-enter clinical trials. The group estimated that globally more than 244,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year’s meeting was focused on advances in the following areas: neuromodulation in Europe, Asia, and Australia; cutting-edge technologies, closed loop DBS, DBS tele-health, neuroethics, lesion therapy, interventional psychiatry, and adaptive DBS.

Summary: In vivo single-unit recordings distinguish the basal spiking properties of neurons in different experimental settings and disease states. Here, we examined over 300 spike trains recorded from Purkinje cells and cerebellar nuclei neurons to test whether data sampling approaches influence the extraction of rich descriptors of firing properties. Our analyses included neurons recorded in awake and anesthetized control mice, and disease models of ataxia, dystonia, and tremor. We find that recording duration circumscribes overall representations of firing rate and pattern. Notably, shorter recording durations skew estimates for global firing rate variability toward lower values. We also find that only some populations of neurons in the same mouse are more similar to each other than to neurons recorded in different mice. These data reveal that recording duration and approach are primary considerations when interpreting task-independent single neuron firing properties. If not accounted for, group differences may be concealed or exaggerated.

Deep brain stimulation (DBS) has potential for several movement disorders. Here the authors show that DBS improves motor function in a mouse model of ataxia.

Essential tremor is the most common pathological tremor, with a prevalence of 6.3% in people over 65 years of age. This disorder interferes with a patient’s ability to carry out activities of daily living independently, and treatment with medical and surgical interventions is often insufficient or contraindicated. Mechanical orthoses have not been widely adopted by patients due to discomfort and lack of discretion. Over the past 30 years, peripheral electrical stimulation has been investigated as a possible treatment for patients who have not found other treatment options to be satisfactory, with wearable devices revolutionizing this emerging approach in recent years. In this paper, an overview of essential tremor and its current medical and surgical treatment options are presented. Following this, tremor detection, measurement and characterization methods are explored with a focus on the measurement options that can be incorporated into wearable devices. Then, novel interventions for essential tremor are described, with a detailed review of open and closed-loop peripheral electrical stimulation methods. Finally, discussion of the need for wearable closed-loop peripheral electrical stimulation devices for essential tremor, approaches in their implementation, and gaps in the literature for further research are presented.

Cognitive processes involve precisely coordinated neuronal communications between multiple cerebral cortical structures in a task specific manner. Rich new evidence now implicates the cerebellum in cognitive functions. There is general agreement that cerebellar cognitive function involves interactions between the cerebellum and cerebral cortical association areas. Traditional views assume reciprocal interactions between one cerebellar and one cerebral cortical site, via closed-loop connections. We offer evidence supporting a new perspective that assigns the cerebellum the role of a coordinator of communication. We propose that the cerebellum participates in cognitive function by modulating the coherence of neuronal oscillations to optimize communications between multiple cortical structures in a task specific manner.

Current closed-loop deep brain stimulation (DBS) devices can generally tackle one disorder. This paper presents the design and evaluation of a multi-disease closed-loop DBS device that can sense multiple brain biomarkers, detect a disorder, and adaptively deliver electrical stimulation pulses based on the disease state. The device consists of: (i) a neural sensor, (ii) a controller involving a feature extractor, a disease classifier, and a control strategy, and (iii) neural stimulator. The neural sensor records and processes local field potentials and spikes from within the brain using two low-frequency and high-frequency channels. The feature extractor digitally processes the output of the neural sensor, and extracts five potential biomarkers: alpha, beta, slow gamma, high-frequency oscillations, and spikes. The disease classifier identifies the type of the neurological disorder through an analysis of the biomarkers' amplitude features. The control strategy considers the disease state and supplies the stimulation settings to the neural stimulator. Both the disease classifier and control strategy are based on fuzzy algorithms. The neural stimulator generates electrical stimulation pulses according to the control commands, and delivers them to the target area of the brain. The device can generate current stimulation pulses with specific amplitude, frequency, and duration. The fabricated device has the maximum radius of 15 mm. Its total weight including the circuit board, battery and battery holder is 5.1 g. The performance of the integrated device has been evaluated through six bench and in-vitro experiments. The experimental results are presented, analyzed, and discussed. Six bench and in-vitro experiments were conducted using sinusoidal, normal pre-recorded, and diseased neural signals representing normal, epilepsy, depression and PD conditions. The results obtained through these tests indicate the successful neural sensing, classification, control, and neural stimulating performance.

Tremor is the most common movement disorder. Several drugs reduce tremor severity, but no cures are available. Propranolol, a β-adrenergic receptor blocker, is the leading treatment for tremor. However, the in vivo circuit mechanisms by which propranolol decreases tremor remain unclear. Here, we test whether propranolol modulates activity in the cerebellum, a key node in the tremor network. We investigated the effects of propranolol in healthy control mice and Car8wdl/wdl mice, which exhibit pathophysiological tremor and ataxia due to cerebellar dysfunction. Propranolol reduced physiological tremor in control mice and reduced pathophysiological tremor in Car8wdl/wdl mice to control levels. Open field and footprinting assays showed that propranolol did not correct ataxia in Car8wdl/wdl mice. In vivo recordings in awake mice revealed that propranolol modulates the spiking activity of control and Car8wdl/wdl Purkinje cells. Recordings in cerebellar nuclei neurons, the targets of Purkinje cells, also revealed altered activity in propranolol-treated control and Car8wdl/wdl mice. Next, we tested whether propranolol reduces tremor through β1 and β2 adrenergic receptors. Propranolol did not change tremor amplitude or cerebellar nuclei activity in β1 and β2 null mice or Car8wdl/wdl mice lacking β1 and β2 receptor function. These data show that propranolol can modulate cerebellar circuit activity through β-adrenergic receptors and may contribute to tremor therapeutics.

The antidepressant actions of deep brain stimulation (DBS) are associated with progressive neuroadaptations within the mood network, modulated in part, by neurotrophic mechanisms. We investigated the antidepressant-like effects of chronic nucleus accumbens (NAc) DBS and its association with change in glycogen synthase kinase 3 (GSK3) and mammalian target of rapamycin (mTOR) expression in the infralimbic cortex (IL), and the dorsal (dHIP) and ventral (vHIP) subregions of the hippocampus of antidepressant resistant rats. Antidepressant resistance was induced via daily injection of adrenocorticotropic hormone (ACTH; 100 μg/day; 15 days) and confirmed by non-response to tricyclic antidepressant treatment (imipramine, 10 mg/kg). Portable microdevices provided continuous bilateral NAc DBS (130 Hz, 200 μA, 90 μs) for 7 days. A control sham electrode group was included, together with ACTH- and saline-treated control groups. Home cage monitoring, open field, sucrose preference, and, forced swim behavioral tests were performed. Post-mortem levels of GSK3 and mTOR, total and phosphorylated, were determined with Western blot. As previously reported, ACTH treatment blocked the immobility-reducing effects of imipramine in the forced swim test. In contrast, treatment with either active DBS or sham electrode placement in the NAc significantly reduced forced swim immobility time in ACTH-treated animals. This was associated with increased homecage activity in the DBS and sham groups relative to ACTH and saline groups, however, no differences in locomotor activity were observed in the open field test, nor were any group differences seen for sucrose consumption across groups. The antidepressant-like actions of NAc DBS and sham electrode placements were associated with an increase in levels of IL and vHIP phospho-GSK3β and phospho-mTOR, however, no differences in these protein levels were observed in the dHIP region. These data suggest that early response to electrode placement in the NAc, irrespective of whether active DBS or sham, has antidepressant-like effects in the ACTH-model of antidepressant resistance associated with distal upregulation of phospho-GSK3β and phospho-mTOR in the IL and vHIP regions of the mood network.

Abstract Background Purkinje cells play a central role in establishing the cerebellar circuit. Accordingly, disrupting Purkinje cell development impairs cerebellar morphogenesis and motor function. In the Car8 wdl mouse model of hereditary ataxia, severe motor deficits arise despite the cerebellum overcoming initial defects in size and morphology. Methods To resolve how this compensation occurs, we asked how the loss of carbonic anhydrase 8 (CAR8), a regulator of IP3R1 Ca2+ signaling in Purkinje cells, alters cerebellar development in Car8 wdl mice. Using a combination of histological, physiological, and behavioral analyses, we determined the extent to which the loss of CAR8 affects cerebellar anatomy, neuronal firing, and motor coordination during development. Results Our results reveal that granule cell proliferation is reduced in early postnatal mutants, although by the third postnatal week there is enhanced and prolonged proliferation, plus an upregulation of Sox2 expression in the inner EGL. Modified circuit patterning of Purkinje cells and Bergmann glia accompany these granule cell adjustments. We also find that although anatomy eventually normalizes, the abnormal activity of neurons and muscles persists. Conclusions Our data show that losing CAR8 only transiently restricts cerebellar growth, but permanently damages its function. These data support two current hypotheses about cerebellar development and disease: (1) Sox2 expression may be upregulated at sites of injury and contribute to the rescue of cerebellar structure and (2) transient delays to developmental processes may precede permanent motor dysfunction. Furthermore, we characterize waddles mutant mouse morphology and behavior during development and propose a Sox2-positive, cell-mediated role for rescue in a mouse model of human motor diseases.

Most of the current closed-loop deep brain stimulation (DBS) devices use a single biomarker in their feedback loop, which may limit their performance and applications. This paper presents the design, fabrication, and validation of a programmable multi-biomarker neural sensor which can be integrated into closed-loop DBS devices. The device is capable of sensing a combination of low-frequency (7–45 Hz), and high-frequency (200–1000 Hz) neural signals. The signals can be amplified with a digitally programmable gain within the range of 50–100 dB. The neural signals can be stored into a local memory for processing and validation. The sensing and storage functions are implemented via a combination of analog and digital circuits involving pre-amplifiers, filters, programmable post-amplifiers, microcontroller, digital potentiometer, and flash memory. The device is fabricated, and its performance is validated through: 1) bench tests using sinusoidal and pre-recorded neural signals; 2) in-vitro tests using pre-recorded neural signals in saline solution; and 3) in-vivo tests by recording neural signals from freely moving laboratory mice. The animals were implanted with a PlasticsOne electrode, and recording was conducted after recovery from the electrode implantation surgery. The experimental results are presented and discussed confirming the successful operation of the device. The size and weight of the device enable tetherless back-mountable use in pre-clinical trials.

Respiration is controlled by central pattern generating circuits in the brain stem, whose activity can be modulated by inputs from other brain areas to adapt respiration to autonomic and behavioral demands. The cerebellum is known to be part of the neuronal circuitry activated during respiratory challenges, such as hunger for air, but has not been found to be involved in the control of spontaneous, unobstructed breathing (eupnea). Here we applied a measure of intrinsic rhythmicity, the CV2, which evaluates the similarity of subsequent intervals and is thus sensitive to changes in rhythmicity at the temporal resolution of individual respiratory intervals. The variability of intrinsic respiratory rhythmicity was reduced in a mouse model of cerebellar ataxia compared to their healthy littermates. Irrespective of that difference, the average respiratory rate and the average coefficient of variation (CV) were comparable between healthy and ataxic mice. We argue that these findings are consistent with a proposed role of the cerebellum in modulating the duration of individual respiratory intervals, which could serve the purpose of coordinating respiration with other rhythmic orofacial movements, such as fluid licking and swallowing.

Purkinje cell microcircuits perform diverse functions using widespread inputs from the brain and spinal cord. The formation of these functional circuits depends on developmental programs and molecular pathways that organize mossy fiber afferents from different sources into a complex and precisely patterned map within the granular layer of the cerebellum. During development, Purkinje cell zonal patterns are thought to guide mossy fiber terminals into zones. However, the molecular mechanisms that mediate this process remain unclear. Here, we used knockout mice to test whether Eph/ephrin signaling controls Purkinje cell-mossy fiber interactions during cerebellar circuit formation. Loss of ephrin-A2 and ephrin-A5 disrupted the patterning of spinocerebellar terminals into discrete zones. Zone territories in the granular layer that normally have limited spinocerebellar input contained ectopic terminals in ephrin-A2−/−;ephrin-A5−/− double knockout mice. However, the overall morphology of the cerebellum, lobule position, and Purkinje cell zonal patterns developed normally in the ephrin-A2−/−;ephrin-A5−/− mutant mice. This work suggests that communication between Purkinje cell zones and mossy fibers during postnatal development allows contact-dependent molecular cues to sharpen the innervation of sensory afferents into functional zones.

Duchenne muscular dystrophy (DMD) is a debilitating and ultimately lethal disease involving progressive muscle degeneration and neurological dysfunction. DMD is caused by mutations in the dystrophin gene, which result in extremely low or total loss of dystrophin protein expression. In the brain, dystrophin is heavily localized to cerebellar Purkinje cells, which control motor and non-motor functions. In vitro experiments in mouse Purkinje cells revealed that loss of dystrophin leads to low firing rates and high spiking variability. However, it is still unclear how the loss of dystrophin affects cerebellar function in the intact brain. Here, we used in vivo electrophysiology to record Purkinje cells and cerebellar nuclear neurons in awake and anesthetized female mdx (also known as Dmd) mice. Purkinje cell simple spike firing rate is significantly lower in mdx mice compared to controls. Although simple spike firing regularity is not affected, complex spike regularity is increased in mdx mutants. Mean firing rate in cerebellar nuclear neurons is not altered in mdx mice, but their local firing pattern is irregular. Based on the relatively well-preserved cytoarchitecture in the mdx cerebellum, our data suggest that faulty signals across the circuit between Purkinje cells and cerebellar nuclei drive the abnormal firing activity. The in vivo requirements of dystrophin during cerebellar circuit communication could help explain the motor and cognitive anomalies seen in individuals with DMD. This article has an associated First Person interview with the first author of the paper.

The cerebellum is well-established as a primary center for controlling sensorimotor functions. However, recent experiments have demonstrated additional roles for the cerebellum in higher-order cognitive functions such as language, emotion, reward, social behavior, and working memory. Based on the diversity of behaviors that it can influence, it is therefore not surprising that cerebellar dysfunction is linked to motor diseases such as ataxia, dystonia, tremor, and Parkinson’s disease as well to non-motor disorders including autism spectrum disorders (ASD), schizophrenia, depression, and anxiety. Regardless of the condition, there is a growing consensus that developmental disturbances of the cerebellum may be a central culprit in triggering a number of distinct pathophysiological processes. Here, we consider how cerebellar malformations and neuronal circuit wiring impact brain function and behavior during development. We use the cerebellum as a model to discuss the expanding view that local integrated brain circuits function within the context of distributed global networks to communicate the computations that drive complex behavior. We highlight growing concerns that neurological and neuropsychiatric diseases with severe behavioral outcomes originate from developmental insults to the cerebellum.

Dystonia is thought to be driven by impairments in cerebellar signalling. The authors use a mouse genetic approach to silence excitatory transmission in the inferior olive to cerebellum pathway, resulting in dystonia-like signs in the animals which can be alleviated using DBS stimulation of the pathway.

Summary: The cerebellum has long been implicated in tasks involving precise temporal control, especially in the coordination of movements. Here we asked whether the cerebellum represents temporal aspects of oscillatory neuronal activity, measured as instantaneous phase and difference between instantaneous phases of oscillations in two cerebral cortical areas involved in cognitive function. We simultaneously recorded Purkinje cell (PC) single-unit spike activity in cerebellar lobulus simplex (LS) and Crus I and local field potential (LFP) activity in the medial prefrontal cortex (mPFC) and dorsal hippocampus CA1 region (dCA1). Purkinje cells in cerebellar LS and Crus I differentially represented specific phases and phase differences of mPFC and dCA1 LFP oscillations in a frequency-specific manner, suggesting a site- and frequency-specific cerebellar representation of temporal aspects of neuronal oscillations in non-motor cerebral cortical areas. These findings suggest that cerebellar interactions with cerebral cortical areas involved in cognitive functions might involve temporal coordination of neuronal oscillations. : The cerebellum has long been implicated in tasks involving precise temporal control, especially in the coordination of movements. McAfee et al. show that the cerebellar principal neurons, Purkinje cells, represent precise temporal information about the phase and phase differences of neuronal oscillations occurring in two non-motor-related cerebral cortical structures. Keywords: neuronal oscillation, cerebro-cerebellar interaction, oscillation phase, phase difference

The brain contains a large diversity of unique cell types that use specific genetic programs to control development and instruct the intricate wiring of sensory, motor, and cognitive brain regions. In addition to their cellular diversity and specialized connectivity maps, each region’s dedicated function is also expressed in their characteristic gross external morphologies. The folds on the surface of the cerebral cortex and cerebellum are classic examples. But, to what extent does structure relate to function and at what spatial scale? We discuss the mechanisms that sculpt functional brain maps and external morphologies. We also contrast the cryptic structural defects in conditions such as autism spectrum disorders to the overt microcephaly after Zika infections, taking into consideration that both diseases disrupt proper cognitive development. The data indicate that dynamic processes shape all brain areas to fit into jigsaw-like patterns. The patterns in each region reflect circuit connectivity, which ultimately supports local signal processing and accomplishes multi-areal integration of information processing to optimize brain functions.

Neurological diseases are especially devastating when they involve neurodegeneration. Neuronal destruction is widespread in cognitive disorders such as Alzheimer's and regionally localized in motor disorders such as Parkinson's, Huntington's, and ataxia. But, surprisingly, the onset and progression of these diseases can occur without neurodegeneration. To understand the origins of diseases that do not have an obvious neuropathology, we tested how loss of CAR8, a regulator of IP3R1-mediated Ca2+-signaling, influences cerebellar circuit formation and neural function as movement deteriorates. We found that faulty molecular patterning, which shapes functional circuits called zones, leads to alterations in cerebellar wiring and Purkinje cell activity, but not to degeneration. Rescuing Purkinje cell function improved movement and reducing their Ca2+ influx eliminated ectopic zones. Our findings in Car8wdl mutant mice unveil a pathophysiological mechanism that may operate broadly to impact motor and non-motor conditions that do not involve degeneration.

The cerebellum is the focus of an emergent series of debates because its circuitry is now thought to encode an unexpected level of functional diversity. The flexibility that is built into the cerebellar circuit allows it to participate not only in motor behaviors involving coordination, learning, and balance but also in non-motor behaviors such as cognition, emotion, and spatial navigation. In accordance with the cerebellum’s diverse functional roles, when these circuits are altered because of disease or injury, the behavioral outcomes range from neurological conditions such as ataxia, dystonia, and tremor to neuropsychiatric conditions, including autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder. Two major questions arise: what types of cells mediate these normal and abnormal processes, and how might they accomplish these seemingly disparate functions? The tiny but numerous cerebellar granule cells may hold answers to these questions. Here, we discuss recent advances in understanding how the granule cell lineage arises in the embryo and how a stem cell niche that replenishes granule cells influences wiring when the postnatal cerebellum is injured. We discuss how precisely coordinated developmental programs, gene expression patterns, and epigenetic mechanisms determine the formation of synapses that integrate multi-modal inputs onto single granule cells. These data lead us to consider how granule cell synaptic heterogeneity promotes sensorimotor and non-sensorimotor signals in behaving animals. We discuss evidence that granule cells use ultrafast neurotransmission that can operate at kilohertz frequencies. Together, these data inspire an emerging view for how granule cells contribute to the shaping of complex animal behaviors.