57 results found
Brickley S, Zirpel F, 2019, Developing more effective seizure therapies requires more selective drugs, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 597, Pages: 4123-4124, ISSN: 0022-3751
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.
Brickley SG, Wisden W, Franks NP, 2018, Modulation of GABA-A receptor function and sleep, Current Opinion in Physiology, Vol: 2, Pages: 51-57, ISSN: 2468-8673
The intravenous general anaesthetics (propofol & etomidate), the barbiturates, steroids (e.g. alphaxalone, allopregnanalone), the benzodiazepines and the widely prescribed ‘sleeping pill’, the imidazopyridine zolpidem, are all positive allosteric modulators (PAMs) of GABAA receptors. PAMs enhance ongoing GABAergic communication between neurons. For treating primary insomnia, zolpidem remains a gold-standard medication — it reduces the latency to NREM sleep with a rapid onset and short half-life, leading to relatively few hangover effects. In this review, we discuss the role of the different GABAA receptor subtypes in the action of sleep-promoting drugs. Certain neuronal hub areas exert disproportionate effects on the brain's vigilance states. For example, injecting GABAA agonists and PAMs into the mesopontine tegmental anaesthesia area (MPTA) induces an anaesthetic-like state. Similarly, by selectively increasing the GABA drive onto arousal-promoting nuclei, such as the histaminergic neurons in the tuberomammillary nucleus, a more natural NREM-like sleep emerges. Some patients suffering from idiopathic hypersomnia have an unidentified GABAA receptor PAM in their cerebral spinal fluid. Treating these patients with benzodiazepine PAM site antagonists improves their symptoms. More knowledge of endogenous GABAA receptor PAMs could provide insight into sleep physiology.
Houston C, Diamanti E, Diamantaki M, et al., 2017, Exploring the significance of morphological diversity for cerebellar granule cell excitability, Scientific Reports, Vol: 7, ISSN: 2045-2322
The relatively simple and compact morphology of cerebellar granule cells (CGCs) has led to the view that heterogeneity in CGC shape has negligible impact upon the integration of mossy fibre (MF) information. Following electrophysiological recording, 3D models were constructed from high-resolution imaging data to identify morphological features that could influence the coding of MF input patterns by adult CGCs. Quantification of MF and CGC morphology provided evidence that CGCs could be connected to the multiple rosettes that arise from a single MF input. Predictions from our computational models propose that MF inputs could be more densely encoded within the CGC layer than previous models suggest. Moreover, those MF signals arriving onto the dendrite closest to the axon will generate greater CGC excitation. However, the impact of this morphological variability on MF input selectivity will be attenuated by high levels of CGC inhibition providing further flexibility to the MF → CGC pathway. These features could be particularly important when considering the integration of multimodal MF sensory input by individual CGCs.
Brickley SG, Ye Z, Yu X, et al., 2017, Fast and slow inhibition in the visual thalamus is influenced by allocating GABAA receptors with different gamma subunits, Frontiers in Cellular Neuroscience, Vol: 11, ISSN: 1662-5102
Cell-type specific differences in the kinetics of inhibitory postsynaptic conductance changes (IPSCs) are believed to impact upon network dynamics throughout the brain. Much attention has focused on how GABAA receptor (GABAAR) α and β subunit diversity will influence IPSC kinetics, but less is known about the influence of the γ subunit. We have examined whether GABAAR γ subunit heterogeneity influences IPSC properties in the thalamus. The γ2 subunit gene was deleted from GABAARs selectively in the dorsal lateral geniculate nucleus (dLGN). The removal of the γ2 subunit from the dLGN reduced the overall spontaneous IPSC (sIPSC) frequency across all relay cells and produced an absence of IPSCs in a subset of relay neurons. The remaining slower IPSCs were both insensitive to diazepam and zinc indicating the absence of the γ2 subunit. Because these slower IPSCs were potentiated by methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), we propose these IPSCs involve γ1 subunit-containing GABAAR activation. Therefore, γ subunit heterogeneity appears to influence the kinetics of GABAAR-mediated synaptic transmission in the visual thalamus in a cell-selective manner. We suggest that activation of γ1 subunit-containing GABAARs give rise to slower IPSCs in general, while faster IPSCs tend to be mediated by γ2 subunit-containing GABAARs.
Jager P, Ye Z, Yu X, et al., 2016, Tectal-derived interneurons contribute to phasic and tonic inhibition in the visual thalamus, Nature Communications, Vol: 7, ISSN: 2041-1723
The release of GABA from local interneurons in the dorsal lateral geniculate nucleus (dLGN-INs) provides inhibitory control during visual processing within the thalamus. It is commonly assumed that this important class of interneurons originates from within the thalamic complex, but we now show that during early postnatal development Sox14/Otx2-expressing precursor cells migrate from the dorsal midbrain to generate dLGN-INs. The unexpected extra-diencephalic origin of dLGN-INs sets them apart from GABAergic neurons of the reticular thalamic nucleus. Using optogenetics we show that at increased firing rates tectal-derived dLGN-INs generate a powerful form of tonic inhibition that regulates the gain of thalamic relay neurons through recruitment of extrasynaptic high-affinity GABAA receptors. Therefore, by revising the conventional view of thalamic interneuron ontogeny we demonstrate how a previously unappreciated mesencephalic population controls thalamic relay neuron excitability.
Wisden W, Uygun DS, Ye Z, et al., 2016, Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons, Journal of Neuroscience, Vol: 36, Pages: 11171-11184, ISSN: 0270-6474
Zolpidem, a GABAA receptor-positive modulator, is the gold-standard drug for treating insomnia. Zolpidem prolongs IPSCs to decrease sleep latency and increase sleep time, effects that depend on α2 and/or α3 subunit-containing receptors. Compared with natural NREM sleep, zolpidem also decreases the EEG power, an effect that depends on α1 subunit-containing receptors, and which may make zolpidem-induced sleep less optimal. In this paper, we investigate whether zolpidem needs to potentiate only particular GABAergic pathways to induce sleep without reducing EEG power. Mice with a knock-in F77I mutation in the GABAA receptor γ2 subunit gene are zolpidem-insensitive. Using these mice, GABAA receptors in the frontal motor neocortex and hypothalamic (tuberomammillary nucleus) histaminergic-neurons of γ2I77 mice were made selectively sensitive to zolpidem by genetically swapping the γ2I77 subunits with γ2F77 subunits. When histamine neurons were made selectively zolpidem-sensitive, systemic administration of zolpidem shortened sleep latency and increased sleep time. But in contrast to the effect of zolpidem on wild-type mice, the power in the EEG spectra of NREM sleep was not decreased, suggesting that these EEG power-reducing effects of zolpidem do not depend on reduced histamine release. Selective potentiation of GABAA receptors in the frontal cortex by systemic zolpidem administration also reduced sleep latency, but less so than for histamine neurons. These results could help with the design of new sedatives that induce a more natural sleep.
Wisden W, Yu X, Ye Z, et al., 2016, Histamine and gamma-amino butyric acid co-transmission promotes arousal, 23rd Congress of the European-Sleep-Research-Society, Publisher: WILEY-BLACKWELL, Pages: 26-26, ISSN: 0962-1105
Yu X, Zhiwen Y, Houston CM, et al., 2015, Wakefulness is governed by GABA and histamine co-transmission, Neuron, Vol: 87, Pages: 164-178, ISSN: 0896-6273
Histaminergic neurons in the tuberomammilary nucleus (TMN) of the hypothalamus form a widely projecting, wake-active network that sustains arousal. Yet most histaminergic neurons contain GABA. Selective siRNA knockdown of the vesicular GABA transporter (vgat, SLC32A1) in histaminergic neurons produced hyperactive mice with an exceptional amount of sustained wakefulness. Ablation of the vgat gene throughout the TMN further sharpened this phenotype. Optogenetic stimulation in the caudate-putamen and neocortex of “histaminergic” axonal projections from the TMN evoked tonic (extrasynaptic) GABAA receptor Cl− currents onto medium spiny neurons and pyramidal neurons. These currents were abolished following vgat gene removal from the TMN area. Thus wake-active histaminergic neurons generate a paracrine GABAergic signal that serves to provide a brake on overactivation from histamine, but could also increase the precision of neocortical processing. The long range of histamine-GABA axonal projections suggests that extrasynaptic inhibition will be coordinated over large neocortical and striatal areas.
Steinberg EA, Wafford KA, Brickley SG, et al., 2015, The role of K-2P channels in anaesthesia and sleep, Pflugers Archiv-European Journal of Physiology, Vol: 467, Pages: 907-916, ISSN: 1432-2013
MacKenzie G, Franks NP, Brickley SG, 2015, Two-pore domain potassium channels enable action potential generation in the absence of voltage-gated potassium channels, PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, Vol: 467, Pages: 989-999, ISSN: 0031-6768
Zhang Z, Ferretti V, Guentan I, et al., 2015, Neuronal ensembles sufficient for recovery sleep and the sedative actions of alpha(2) adrenergic agonists, Nature Neuroscience, Vol: 18, Pages: 553-561, ISSN: 1546-1726
Do sedatives engage natural sleep pathways? It is usually assumed that anesthetic-induced sedation and loss of righting reflex (LORR) arise by influencing the same circuitry to lesser or greater extents. For the α2 adrenergic receptor agonist dexmedetomidine, we found that sedation and LORR were in fact distinct states, requiring different brain areas: the preoptic hypothalamic area and locus coeruleus (LC), respectively. Selective knockdown of α2A adrenergic receptors from the LC abolished dexmedetomidine-induced LORR, but not sedation. Instead, we found that dexmedetomidine-induced sedation resembled the deep recovery sleep that follows sleep deprivation. We used TetTag pharmacogenetics in mice to functionally mark neurons activated in the preoptic hypothalamus during dexmedetomidine-induced sedation or recovery sleep. The neuronal ensembles could then be selectively reactivated. In both cases, non-rapid eye movement sleep, with the accompanying drop in body temperature, was recapitulated. Thus, α2 adrenergic receptor–induced sedation and recovery sleep share hypothalamic circuitry sufficient for producing these behavioral states.
Wisden W, Yu X, Zecharia A, et al., 2014, Circadian Factor BMAL1 in Histaminergic Neurons Regulates Sleep Architecture, Current Biology, Vol: 24, Pages: 2838-2844, ISSN: 1879-0445
Circadian clocks allow anticipation of daily environmental changes [ 1 ]. The suprachiasmatic nucleus (SCN) houses the master clock, but clocks are also widely expressed elsewhere in the body [ 1 ]. Although some peripheral clocks have established roles [ 1 ], it is unclear what local brain clocks do [ 2, 3 ]. We tested the contribution of one putative local clock in mouse histaminergic neurons in the tuberomamillary nucleus to the regulation of the sleep-wake cycle. Histaminergic neurons are silent during sleep, and start firing after wake onset [ 4–6 ]; the released histamine, made by the enzyme histidine decarboxylase (HDC), enhances wakefulness [ 7–11 ]. We found that hdc gene expression varies with time of day. Selectively deleting the Bmal1 (also known as Arntl or Mop3 [ 12 ]) clock gene from histaminergic cells removes this variation, producing higher HDC expression and brain histamine levels during the day. The consequences include more fragmented sleep, prolonged wake at night, shallower sleep depth (lower nonrapid eye movement [NREM] δ power), increased NREM-to-REM transitions, hindered recovery sleep after sleep deprivation, and impaired memory. Removing BMAL1 from histaminergic neurons does not, however, affect circadian rhythms. We propose that for mammals with polyphasic/nonwake consolidating sleep, the local BMAL1-dependent clock directs appropriately timed declines and increases in histamine biosynthesis to produce an appropriate balance of wake and sleep within the overall daily cycle of rest and activity specified by the SCN.
Baker R, Gent TC, Yang Q, et al., 2014, Altered activity in the central medial thalamus precedes changes in the neocortex during transitions into both sleep and propofol anesthesia, The Journal of Neuroscience, Vol: 34, Pages: 13326-13335, ISSN: 0270-6474
How general anesthetics cause loss of consciousness is unknown. Some evidence points toward effects on the neocortex causing “top-down” inhibition, whereas other findings suggest that these drugs act via subcortical mechanisms, possibly selectively stimulating networks promoting natural sleep. To determine whether some neuronal circuits are affected before others, we used Morlet wavelet analysis to obtain high temporal resolution in the time-varying power spectra of local field potentials recorded simultaneously in discrete brain regions at natural sleep onset and during anesthetic-induced loss of righting reflex in rats. Although we observed changes in the local field potentials that were anesthetic-specific, there were some common changes in high-frequency (20–40 Hz) oscillations (reductions in frequency and increases in power) that could be detected at, or before, sleep onset and anesthetic-induced loss of righting reflex. For propofol and natural sleep, these changes occur first in the thalamus before changes could be detected in the neocortex. With dexmedetomidine, the changes occurred simultaneously in the thalamus and neocortex. In addition, the phase relationships between the low-frequency (1–4 Hz) oscillations in thalamic nuclei and neocortical areas are essentially the same for natural sleep and following dexmedetomidine administration, but a sudden change in phase, attributable to an effect in the central medial thalamus, occurs at the point of dexmedetomidine loss of righting reflex. Our data are consistent with the central medial thalamus acting as a key hub through which general anesthesia and natural sleep are initiated.
Ye Z, McGee TP, Houston C, et al., 2013, The contribution of delta subunit-containing GABA(A) receptors to phasic and tonic conductance changes in cerebellum thalamus and neocortex, FRONTIERS IN NEURAL CIRCUITS, Vol: 7, ISSN: 1662-5110
McGee TP, Houston CM, Brickley SG, 2013, Copper Block of Extrasynaptic GABA(A) Receptors in the Mature Cerebellum and Striatum, JOURNAL OF NEUROSCIENCE, Vol: 33, Pages: 13431-13435, ISSN: 0270-6474
Zecharia AY, Yu X, Götz T, et al., 2012, GABAergic inhibition of histaminergic neurons regulates active waking but not the sleep-wake switch or propofol-induced loss of consciousness., J Neurosci, Vol: 32, Pages: 13062-13075
The activity of histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus correlates with an animal's behavioral state and maintains arousal. We examined how GABAergic inputs onto histaminergic neurons regulate this behavior. A prominent hypothesis, the "flip-flop" model, predicts that increased and sustained GABAergic drive onto these cells promotes sleep. Similarly, because of the histaminergic neurons' key hub-like place in the arousal circuitry, it has also been suggested that anesthetics such as propofol induce loss of consciousness by acting primarily at histaminergic neurons. We tested both these hypotheses in mice by genetically removing ionotropic GABA(A) or metabotropic GABA(B) receptors from histidine decarboxylase-expressing neurons. At the cellular level, histaminergic neurons deficient in synaptic GABA(A) receptors were significantly more excitable and were insensitive to the anesthetic propofol. At the behavioral level, EEG profiles were recorded in nontethered mice over 24 h. Surprisingly, GABAergic transmission onto histaminergic neurons had no effect in regulating the natural sleep-wake cycle and, in the case of GABA(A) receptors, for propofol-induced loss of righting reflex. The latter finding makes it unlikely that the histaminergic TMN has a central role in anesthesia. GABA(B) receptors on histaminergic neurons were dispensable for all behaviors examined. Synaptic inhibition of histaminergic cells by GABA(A) receptors, however, was essential for habituation to a novel environment.
Franks N, Brickley S, Wisden W, 2012, The relationship between natural sleep and general anaesthesia, 21st Congress of the European-Sleep-Research-Society, Publisher: WILEY-BLACKWELL, Pages: 47-47, ISSN: 0962-1105
Houston CM, McGee TP, MacKenzie G, et al., 2012, Are Extrasynaptic GABA(A) Receptors Important Targets for Sedative/Hypnotic Drugs?, JOURNAL OF NEUROSCIENCE, Vol: 32, Pages: 3887-3897, ISSN: 0270-6474
Brickley SG, Mody I, 2012, Extrasynaptic GABA(A) Receptors: Their Function in the CNS and Implications for Disease, NEURON, Vol: 73, Pages: 23-34, ISSN: 0896-6273
Houston CM, Brickley SG, 2011, Cerebellar Golgi cell inhibition gets slowly more complicated, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 589, Pages: 4403-4403, ISSN: 0022-3751
Bright DP, Renzi M, Bartram J, et al., 2011, Profound Desensitization by Ambient GABA Limits Activation of delta-Containing GABA(A) Receptors during Spillover, JOURNAL OF NEUROSCIENCE, Vol: 31, Pages: 753-763, ISSN: 0270-6474
Pang DSJ, Robledo CJ, Carr DR, et al., 2009, An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 106, Pages: 17546-17551, ISSN: 0027-8424
Zecharia AY, Nelson LE, Gent TC, et al., 2009, The Involvement of Hypothalamic Sleep Pathways in General Anesthesia: Testing the Hypothesis Using the GABA(A) Receptor beta(3)N265M Knock-In Mouse, JOURNAL OF NEUROSCIENCE, Vol: 29, Pages: 2177-2187, ISSN: 0270-6474
Bright DP, Brickley SG, 2008, Acting locally but sensing globally: impact of GABAergic synaptic plasticity on phasic and tonic inhibition in the thalamus, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 586, Pages: 5091-5099, ISSN: 0022-3751
Brickley SG, Aller MI, Sandu C, et al., 2007, TASK-3 two-pore domain potassium channels enable sustained high-frequency firing in cerebellar granule neurons, JOURNAL OF NEUROSCIENCE, Vol: 27, Pages: 9329-9340, ISSN: 0270-6474
Bright DP, Aller MI, Brickley SG, 2007, Synaptic release generates a tonic GABA(A) receptor-mediated conductance that modulates burst precision in thalamic relay neurons, JOURNAL OF NEUROSCIENCE, Vol: 27, Pages: 2560-2569, ISSN: 0270-6474
Ahmad-Annuar A, Ciani L, Simeonidis I, et al., 2006, Signaling across the synapse: a role for Wnt and Dishevelled in presynaptic assembly and neurotransmitter release, JOURNAL OF CELL BIOLOGY, Vol: 174, Pages: 127-139, ISSN: 0021-9525
Aller MI, Veale EL, Linden AM, et al., 2005, Modifying the subunit composition of TASK channels alters the modulation of a leak conductance in cerebellar granule neurons, JOURNAL OF NEUROSCIENCE, Vol: 25, Pages: 11455-11467, ISSN: 0270-6474
Chiu CS, Brickley S, Jensen K, et al., 2005, GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum, JOURNAL OF NEUROSCIENCE, Vol: 25, Pages: 3234-3245, ISSN: 0270-6474
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