Paul Chadderton

Developing effective strategies to replace or restore injured neurons could significantly revolutionise the treatment of currently incurable neurodegenerative disorders. Studies have shown that bone marrow-derived cells (BMDCs) can migrate into the brain and fuse with damaged Purkinje neurons (PNs), restoring their structure and function. Yet, despite over two decades of research, the temporal dynamics and functional stability of these fusion events in vivo remain poorly defined, largely due to reliance on static, post-mortem histological analyses that provide only a single snapshot in time. Here, using in vivo two-photon imaging of the intact cerebellum in EGFP-bone marrow chimeric mice, we visualised the dynamics of BMDC-PN interactions both in real time and longitudinally to monitor the physiological characteristics of fused PNs. Notably, we provide definitive evidence that fused cells are not transient but remain stable over extended periods in the living brain. Moreover, we demonstrate sustained transcriptional activity of donor-derived genes within fused PNs, indicating partial or complete functional integration of the BMDC nucleus. Given their accessibility and genetic tractability, BMDCs represent a practical and promising platform for targeted delivery of therapeutic genes to PNs, opening new avenues for treating neurodegenerative disease.

Molecular layer interneurons (MLIs) within the cerebellar cortex mediate feed-forward inhibition onto Purkinje cells, positioning them as pivotal modulators of cerebellar output. We asked how motor patterns and salient sensory input influence MLI population activity during active whisking and tactile interactions. Utilizing two-photon calcium imaging combined with high-speed videography, we examined MLI population dynamics in awake, behaving mice engaged in voluntary whisker movements. Our results demonstrate that during free whisking, MLI population activity reliably tracks whisker position, yielding uniform graded responses that provide stable and precise representations over time. Tactile contact with external stimuli evokes additional activation in a subset of MLIs. Sensory input transiently disrupts the linear relationship between MLI activity and whisker position and may account for rapid synchronous inhibition of Purkinje cell spiking activity following tactile stimulation. These findings indicate that MLIs in Crus 1 maintain an accurate internal model of whisker position which is perturbed upon encountering obstacles. This disruption likely reflects the integration of sensory feedback, disrupting predictive signals that are subsequently passed forward to Purkinje cells. Such signals can alert the brain to novel happenings and be used to update motor commands, thereby contributing to cerebellar function in response to environmental changes.

The brain must maintain a stable world model while rapidly adapting to the environment, but the underlying mechanisms are not known. Here, we posit that cortico-cerebellar loops play a key role in this process. We introduce a computational model of cerebellar networks that learn to drive cortical networks with task-outcome predictions. First, using sensorimotor tasks, we show that cerebellar feedback in the presence of stable cortical networks is sufficient for rapid task acquisition and switching. Next, we demonstrate that, when trained in working memory tasks, the cerebellum can also underlie the maintenance of cognitive-specific dynamics in the cortex, explaining a range of optogenetic and behavioural observations. Finally, using our model, we introduce a systems consolidation theory in which task information is gradually transferred from the cerebellum to the cortex. In summary, our findings suggest that cortico-cerebellar loops are an important component of task acquisition, switching, and consolidation in the brain.

GlyT2-positive interneurons, Golgi and Lugaro cells, reside in the input layer of the cerebellar cortex in a key position to influence information processing. Here, we examine the contribution of GlyT2-positive interneurons to network dynamics in Crus 1 of mouse lateral cerebellar cortex during free whisking. We recorded neuronal population activity using Neuropixels probes before and after chemogenetic downregulation of GlyT2-positive interneurons in male and female mice. Under resting conditions, cerebellar population activity reliably encoded whisker movements. Reductions in the activity of GlyT2-positive cells produced mild increases in neural activity which did not significantly impair these sensorimotor representations. However, reduced Golgi and Lugaro cell inhibition did increase the temporal alignment of local population network activity at the initiation of movement. These network alterations had variable impacts on behavior, producing both increases and decreases in whisking velocity. Our results suggest that inhibition mediated by GlyT2-positive interneurons primarily governs the temporal patterning of population activity, which in turn is required to support downstream cerebellar dynamics and behavioral coordination.

GlyT2-positive interneurons, Golgi and Lugaro cells, reside in the input layer of the cerebellar cortex in a key position to influence information processing. Here, we examine the contribution of GlyT2-positive interneurons to network dynamics in Crus 1 of mouse lateral cerebellar cortex during free whisking. We recorded neuronal population activity using NeuroPixels probes before and after chemogenetic downregulation of GlyT2-positive interneurons. Under resting conditions, cerebellar population activity reliably encoded whisker movements. Reductions in the activity of GlyT2-positive cells produced mild increases in neural activity which did not significantly impair these sensorimotor representations. However, reduced Golgi and Lugaro cell inhibition did increase the temporal alignment of local population network activity at the initiation of movement. These network alterations had variable impacts on behaviour, producing both increases and decreases in whisking velocity. Our results suggest that inhibition mediated by GlyT2-positive interneurons primarily governs the temporal patterning of population activity, which in turn is required to support downstream cerebellar dynamics and behavioural coordination. SIGNIFICANCE STATEMENT: The cerebellum has a simple and conserved structure which has tantalised neurobiologists wishing to understand its function. Here we look at the role of granule cell layer inhibitory interneurons, Golgi and Lugaro cells, in the cerebellar cortex. We selectively turned down the activity of these cells in the awake cerebellum to characterise their influence on network activity and behaviour. We show that downregulation of Golgi and Lugaro cells has very little influence on sensorimotor representations in the cerebellum (i.e., what is represented), but instead modulates the timing of cortical population activity (i.e., when information is represented). Our results indicate that inhibitory interneurons in the granule cell layer are necessary to appropriately pace changes in cerebellar activity to match ongoing behaviour.

Cerebellar computations are necessary for fine behavioural control and are thought to rely on internal probabilistic models performing state estimation. We propose that the cerebellum infers how states contextualise (i.e., interact with) each other, and coordinates extra-cerebellar neuronal dynamics underpinning a range of behaviours. To support this claim, we describe a cerebellar model for state estimation that includes states interactions, and link the underlying inference with the neuronal architecture and dynamics observed empirically. This is formalised using the free energy principle, which provides a dual perspective on a system in terms of both the dynamics of its physical – in this case neuronal – states, and the inference process they entail. As a proof of principle, we simulate cerebellar-dependent synchronisation of whisking and respiration, which are known to be tightly coupled in rodents. In summary, we suggest that cerebellar-dependent contextualisation of behaviour can explain its ubiquitous involvement in most aspects of behaviour.

Behavioural feedback is critical for learning in the cerebral cortex. However, such feedback is often not readily available. How the cerebral cortex learns efficiently despite the sparse nature of feedback remains unclear. Inspired by recent deep learning algorithms, we introduce a systems-level computational model of cerebro-cerebellar interactions. In this model a cerebral recurrent network receives feedback predictions from a cerebellar network, thereby decoupling learning in cerebral networks from future feedback. When trained in a simple sensorimotor task the model shows faster learning and reduced dysmetria-like behaviours, in line with the widely observed functional impact of the cerebellum. Next, we demonstrate that these results generalise to more complex motor and cognitive tasks. Finally, the model makes several experimentally testable predictions regarding cerebro-cerebellar task-specific representations over learning, task-specific benefits of cerebellar predictions and the differential impact of cerebellar and inferior olive lesions. Overall, our work offers a theoretical framework of cerebro-cerebellar networks as feedback decoupling machines.

We studied how histamine and GABA release from axons originating from the hypothalamic tuberomammillary nucleus (TMN) and projecting to the prefrontal cortex (PFC) influence circuit processing. We optostimulated histamine/GABA from genetically defined TMN axons that express the histidine decarboxylase gene (TMN_HDCaxons). Whole-cell recordings from PFC neurons in layer 2/3 of prelimbic, anterior cingulate, and infralimbic regions were used to monitor excitability before and after optostimulated histamine/GABA release in male and female mice. We found that histamine-GABA release influences the PFC through actions on distinct neuronal types: the histamine stimulates fast-spiking interneurons; and the released GABA enhances tonic (extrasynaptic) inhibition on pyramidal cells (PyrNs). For fast-spiking nonaccommodating interneurons, histamine released from TMN_HDCaxons induced additive gain changes, which were blocked by histamine H1 and H2 receptor antagonists. The excitability of other fast-spiking interneurons in the PFC was not altered. In contrast, the GABA released from TMN_HDCaxons predominantly produced divisive gain changes in PyrNs, increasing their resting input conductance, and decreasing the slope of the input–output relationship. This inhibitory effect on PyrNs was not blocked by histamine receptor antagonists but was blocked by GABA_Areceptor antagonists. Across the adult life span (from 3 to 18 months of age), the GABA released from TMN_HDCaxons in the PFC inhibited PyrN excitability significantly more in older mice. For individuals who maintain cognitive performance into later life, the increases in TMN_HDCGABA modulation of PyrNs during aging could enhance information processing and be an adaptive mechanism to buttress cognition.SIGNIFICANCE STATEMENTThe hypothalamus controls arousal state by releasing chemical neurotransmitters throughout the brain to modulate neuronal excitability. Evidence is emerging that the release of multiple types of neurotransmitters may have opposing actions on neuronal populations in key cortical regions. This study demonstrates for the first time that the neurotransmitters histamine and GABA are released in the prefrontal cortex from axons originating from the tuberomammillary nucleus of the hypothalamus. This work demonstrates how hypothalamic modulation of neuronal excitability is maintained throughout adult life, highlighting an unexpected aspect of the aging process that may help maintain cognitive abilities.

Summary: To drive behavior, the cortex must bridge sensory cues with future outcomes. However, the principles by which cortical networks learn such sensory-behavioural transformations remain largely elusive. Here, we posit that the cerebellum assumes a crucial role in driving cortical dynamics, thereby enabling rapid and flexible task acquisition. We introduce a computational model of cerebellar networks which learn to drive cortical networks with task-outcome predictions. First, using sensorimotor tasks we show that cerebellar feedback in the presence of minimal cortical plasticity is suffcient for rapid task acquisition and multiple task switching. Next, we demonstrate that, when trained in working memory tasks, the cerebellum can also underlie the maintenance of cognitive-specific dynamics, explaining a range of optogenetic and behavioural observations. Finally, using our model we introduce a systems consolidation theory in which task information is gradually transferred from the cerebellum to the cortex. In summary, our findings suggest that cortico-cerebellar loops play a pivotal role in task acquisition, switching, and consolidation within the brain.