24 results found
Lucaci D, Yu X, Chadderton P, et al., 2023, Histamine release in the prefrontal cortex excites fast-spiking interneurons while GABA released from the same axons inhibits pyramidal cells, The Journal of Neuroscience, Vol: 43, Pages: 187-198, ISSN: 0270-6474
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 (TMNHDC axons). 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 TMNHDC axons 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 TMNHDC axons 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 GABAA receptor antagonists. Across the adult life span (from 3 to 18 months of age), the GABA released from TMNHDC axons in the PFC inhibited PyrN excitability significantly more in older mice. For individuals who maintain cognitive performance into later life, the increases in TMNHDC GABA modulation of PyrNs during aging could enhance information processing and be an adaptive mechanism to buttress cognition.
Boven E, Pemberton J, Chadderton P, et al., 2023, Cerebro-cerebellar networks facilitate learning through feedback decoupling., Nat Commun, Vol: 14
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.
Barkus C, Bergmann C, Branco T, et al., 2022, Refinements to rodent head fixation and fluid/food control for neuroscience, Journal of Neuroscience Methods, Vol: 381, Pages: 109705-109705, ISSN: 0165-0270
The use of head fixation in mice is increasingly common in research, its use having initially been restricted to the field of sensory neuroscience. Head restraint has often been combined with fluid control, rather than food restriction, to motivate behaviour, but this too is now in use for both restrained and non-restrained animals. Despite this, there is little guidance on how best to employ these techniques to optimise both scientific outcomes and animal welfare. This article summarises current practices and provides recommendations to improve animal wellbeing and data quality, based on a survey of the community, literature reviews, and the expert opinion and practical experience of an international working group convened by the UK's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). Topics covered include head fixation surgery and post-operative care, habituation to restraint, and the use of fluid/food control to motivate performance. We also discuss some recent developments that may offer alternative ways to collect data from large numbers of behavioural trials without the need for restraint. The aim is to provide support for researchers at all levels, animal care staff, and ethics committees to refine procedures and practices in line with the refinement principle of the 3Rs.
Golden CT, Chadderton P, 2022, Psilocybin reduces low frequency oscillatory power and neuronal phase-locking in the anterior cingulate cortex of awake rodents, SCIENTIFIC REPORTS, Vol: 12, ISSN: 2045-2322
Palacios ER, Houghton C, Chadderton P, 2021, Accounting for uncertainty: inhibition for neural inference in the cerebellum, PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 288, ISSN: 0962-8452
Chapuis GA, Chadderton PT, 2018, Using temporal expectation to assess auditory streaming in mice, Frontiers in Behavioral Neuroscience, Vol: 12, ISSN: 1662-5153
Auditory streaming is the process by which environmental sound is segregated intodiscrete perceptual objects. The auditory system has a remarkable capability in thisregard as revealed in psychophysical experiments in humans and other primates.However, little is known about the underlying neuronal mechanisms, in part becauseof the lack of suitable behavioural paradigms in non-primate species. The mouse is anincreasingly popular model for studying the neural mechanisms of perception and actionbecause of the range of molecular tools enabling precise manipulation of neural circuitry.Here we present a novel behavioural task that can be used to assess perceptual aspectsof auditory streaming in head-fixed mice. Animals were trained to detect a target soundin a one of two simultaneously presented, isochronous pure tone sequences. Temporalexpectation was manipulated by presenting the target sound in a particular stream eitherearly (∼2 s) or late (∼4 s) with respect to trial onset in blocks of 25–30 trials. Animalsreached high performance on this task (d’ > 1 overall), and notably their false alarmswere very instructive of their behavioural state. Indeed, false alarm timing was markedlydelayed for late blocks compared to early ones, indicating that the animals associated adifferent context to an otherwise identical stimulus. More finely, we observed that the falsealarms were timed to the onset of the sounds present in the target stream. This suggeststhat the animals could selectively follow the target stream despite the presence of adistractor stream. Extracellular electrophysiological recordings during the task revealedthat sound processing is flexibly modulated in a manner consistent with the optimisationof behavioural outcome. Together, these results indicate that the perceptual streamingcan be inferred via the timing of false alarms in mice, and provide a new paradigm withwhich to investigate neuronal mechanisms of selective attention.
Song JH, Lucaci D, Calangiu I, et al., 2018, Combining mGRASP and optogenetics enables high-resolution functional mapping of descending cortical projections, Cell Reports, Vol: 24, Pages: 1071-1080, ISSN: 2211-1247
We have applied optogenetics and mGRASP, a light microscopy technique that labels synaptic contacts, to map the number and strength of defined corticocollicular (CC) connections. Using mGRASP, we show that CC projections form small, medium, and large synapses, and both the number and the distribution of synapse size vary among the IC regions. Using optogenetics, we show that low-frequency stimulation of CC axons expressing channelrhodopsin produces prolonged elevations of the CC miniature EPSC (mEPSC) rate. Functional analysis of CC mEPSCs reveals small-, medium-, and large-amplitude events that mirror the synaptic distributions observed with mGRASP. Our results reveal that descending ipsilateral projections dominate CC feedback via an increased number of large synaptic contacts, especially onto the soma of IC neurons. This study highlights the feasibility of combining microscopy (i.e., mGRASP) and optogenetics to reveal synaptic weighting of defined projections at the level of single neurons, enabling functional connectomic mapping in diverse neural circuits.
Sollini J, Chapuis GA, Clopath C, et al., 2018, ON-OFF receptive fields in auditory cortex diverge during development and contribute to directional sweep selectivity, Nature Communications, Vol: 9, ISSN: 2041-1723
Neurons in the auditory cortex exhibit distinct frequency tuning to the onset and offset of sounds, but the cause and significance of ON and OFF receptive field (RF) organisation are not understood. Here we demonstrate that distinct ON and OFF frequency tuning is largely absent in immature mouse auditory cortex and is thus a consequence of cortical development. Simulations using a novel implementation of a standard Hebbian plasticity model show that the natural alternation of sound onset and offset is sufficient for the formation of non-overlapping adjacent ON and OFF RFs in cortical neurons. Our model predicts that ON/OFF RF arrangement contributes towards direction selectivity to frequency-modulated tone sweeps, which we confirm by neuronal recordings. These data reveal that a simple and universally accepted learning rule can explain the organisation of ON and OFF RFs and direction selectivity in the developing auditory cortex.
Robins T, Leow CH, Chapuis G, et al., 2017, Dual Frequency Transcranial Ultrasound for Contrast Enhanced Ultrafast Brain Functional Imaging, IEEE International Ultrasonics Symposium (IUS), Publisher: IEEE, ISSN: 1948-5719
Annecchino LA, Morris AR, Copeland CS, et al., 2017, Robotic automation of in vivo two photon targeted whole-cell patch clamp electrophysiology, Neuron, Vol: 95, Pages: 1048-1055.e3, ISSN: 0896-6273
Whole-cell patch-clamp electrophysiological recording is a powerful technique for studying cellular function. While in vivo patch-clamp recording has recently benefited from automation, it is normally performed “blind,” meaning that throughput for sampling some genetically or morphologically defined cell types is unacceptably low. One solution to this problem is to use two-photon microscopy to target fluorescently labeled neurons. Combining this with robotic automation is difficult, however, as micropipette penetration induces tissue deformation, moving target cells from their initial location. Here we describe a platform for automated two-photon targeted patch-clamp recording, which solves this problem by making use of a closed loop visual servo algorithm. Our system keeps the target cell in focus while iteratively adjusting the pipette approach trajectory to compensate for tissue motion. We demonstrate platform validation with patch-clamp recordings from a variety of cells in the mouse neocortex and cerebellum.
Chen S, Augustine GJ, Chadderton P, 2017, Serial processing of kinematic signals by cerebellar circuitry during voluntary whisking., Nat Commun, Vol: 8
Purkinje cells (PCs) in Crus 1 represent whisker movement via linear changes in firing rate, but the circuit mechanisms underlying this coding scheme are unknown. Here we examine the role of upstream inputs to PCs-excitatory granule cells (GCs) and inhibitory molecular layer interneurons-in processing of whisking signals. Patch clamp recordings in GCs reveal that movement is accompanied by changes in mossy fibre input rate that drive membrane potential depolarisation and high-frequency bursting activity at preferred whisker angles. Although individual GCs are narrowly tuned, GC populations provide linear excitatory drive across a wide range of movement. Molecular layer interneurons exhibit bidirectional firing rate changes during whisking, similar to PCs. Together, GC populations provide downstream PCs with linear representations of volitional movement, while inhibitory networks invert these signals. The exquisite sensitivity of neurons at each processing stage enables faithful propagation of kinematic representations through the cerebellum.Cerebellar Purkinje cells (PCs) linearly encode whisker position but the precise circuit mechanisms that generate these signals are not well understood. Here the authors use patch clamp recordings to show that selective tuning of granule cell inputs and bidirectional tuning of interneuron inputs are required to generate the kinematic representations in PCs.
Sollini J, Chadderton P, 2016, Comodulation enhances signal detection via priming of auditory cortical circuits, Journal of Neuroscience, Vol: 36, Pages: 12299-12311, ISSN: 0270-6474
Acoustic environments are composed of complex overlapping sounds that the auditory system is required to segregate into discrete perceptual objects. The functions of distinct auditory processing stations in this challenging task are poorly understood. Here we show a direct role for mouse auditory cortex in detection and segregation of acoustic information. We measured the sensitivity of auditory cortical neurons to brief tones embedded in masking noise. By altering spectrotemporal characteristics of the masker, we reveal that sensitivity to pure tone stimuli is strongly enhanced in coherently modulated broadband noise, corresponding to the psychoacoustic phenomenon comodulation masking release. Improvements in detection were largest following priming periods of noise alone, indicating that cortical segregation is enhanced over time. Transient opsin-mediated silencing of auditory cortex during the priming period almost completely abolished these improvements, suggesting that cortical processing may play a direct and significant role in detection of quiet sounds in noisy environments.
Chen S, Augustine GJ, Chadderton PT, 2016, The cerebellum linearly encodes whisker position during voluntary movement, eLife, Vol: 5, ISSN: 2050-084X
Active whisking is an important model sensorimotor behavior, but the function of thecerebellum in the rodent whisker system is unknown. We have made patch clamp recordings fromPurkinje cells in vivo to identify whether cerebellar output encodes kinematic features of whiskingincluding the phase and set point. We show that Purkinje cell spiking activity changes stronglyduring whisking bouts. On average, the changes in simple spike rate coincide with or slightlyprecede movement, indicating that the synaptic drive responsible for these changes ispredominantly of efferent (motor) rather than re-afferent (sensory) origin. Remarkably, on-goingchanges in simple spike rate provide an accurate linear read-out of whisker set point. Thus, despitereceiving several hundred thousand discrete synaptic inputs across a non-linear dendritic tree,Purkinje cells integrate parallel fiber input to generate precise information about whiskingkinematics through linear changes in firing rate.
Duguid I, Branco T, Chadderton P, et al., 2015, Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition., Proceedings of the National Academy of Sciences of the United States of America, Vol: 112, Pages: 13099-13104, ISSN: 1091-6490
Classical feed-forward inhibition involves an excitation-inhibition sequence that enhances the temporal precision of neuronal responses by narrowing the window for synaptic integration. In the input layer of the cerebellum, feed-forward inhibition is thought to preserve the temporal fidelity of granule cell spikes during mossy fiber stimulation. Although this classical feed-forward inhibitory circuit has been demonstrated in vitro, the extent to which inhibition shapes granule cell sensory responses in vivo remains unresolved. Here we combined whole-cell patch-clamp recordings in vivo and dynamic clamp recordings in vitro to directly assess the impact of Golgi cell inhibition on sensory information transmission in the granule cell layer of the cerebellum. We show that the majority of granule cells in Crus II of the cerebrocerebellum receive sensory-evoked phasic and spillover inhibition prior to mossy fiber excitation. This preceding inhibition reduces granule cell excitability and sensory-evoked spike precision, but enhances sensory response reproducibility across the granule cell population. Our findings suggest that neighboring granule cells and Golgi cells can receive segregated and functionally distinct mossy fiber inputs, enabling Golgi cells to regulate the size and reproducibility of sensory responses.
Chadderton P, Schaefer AT, Williams SR, et al., 2014, Sensory-evoked synaptic integration in cerebellar and cerebral cortical neurons, NATURE REVIEWS NEUROSCIENCE, Vol: 15, Pages: 71-83, ISSN: 1471-003X
Duguid I, Branco T, London M, et al., 2012, Tonic Inhibition Enhances Fidelity of Sensory Information Transmission in the Cerebellar Cortex, JOURNAL OF NEUROSCIENCE, Vol: 32, Pages: 11132-11143, ISSN: 0270-6474
Harris KD, Bartho P, Chadderton P, et al., 2011, How do neurons work together? Lessons from auditory cortex, HEARING RESEARCH, Vol: 271, Pages: 37-53, ISSN: 0378-5955
Saleem AB, Chadderton P, Apergis-Schoute J, et al., 2010, Methods for predicting cortical UP and DOWN states from the phase of deep layer local field potentials, JOURNAL OF COMPUTATIONAL NEUROSCIENCE, Vol: 29, Pages: 49-62, ISSN: 0929-5313
Chadderton P, Agapiou JP, McAlpine D, et al., 2009, The Synaptic Representation of Sound Source Location in Auditory Cortex, JOURNAL OF NEUROSCIENCE, Vol: 29, Pages: 14127-14135, ISSN: 0270-6474
Rancz EA, Ishikawa T, Duguid I, et al., 2007, High-fidelity transmission of sensory information by single cerebellar mossy fibre boutons, NATURE, Vol: 450, Pages: 1245-U12, ISSN: 0028-0836
Loewenstein Y, Mahon S, Chadderton P, et al., 2006, Purkinje cells in awake behaving animals operate at the upstate membrane potential -: Reply, NATURE NEUROSCIENCE, Vol: 9, Pages: 461-461, ISSN: 1097-6256
Loewenstein Y, Mahon S, Chadderton P, et al., 2005, Bistability of cerebellar Purkinje cells modulated by sensory stimulation, NATURE NEUROSCIENCE, Vol: 8, Pages: 202-211, ISSN: 1097-6256
Mittmann W, Chadderton P, Häusser M, 2004, Neuronal microcircuits:: Frequency-dependent flow of inhibition, CURRENT BIOLOGY, Vol: 14, Pages: R837-R839, ISSN: 0960-9822
Chadderton P, Margrie TW, Häusser M, 2004, Integration of quanta in cerebellar granule cells during sensory processing, NATURE, Vol: 428, Pages: 856-860, ISSN: 0028-0836
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