Genetic Techniques and Circuit Analysis

Reaching an understanding of how neuronal circuits work and what they compute is a fundamental aim of neuroscience, perhaps even the most fundamental. We have to both establish the connections between cell types and reversibly manipulate their activity cell-typeselectively. Such work sounds in principle straight-forward, but it has been difficult to achieve. This has now all changed. There has been a quite remarkable development of genetic techniques published in the last years, so that the topic of “Genetic techniques and circuit analysis ” covered by the articles in this Special Issue is truly flourishing. The extremely easy applicability of the channelrhodopsin-2 system (ChR2) in diverse animals and circuit settings has been a phenomenal breakthrough and captured the imagination of the neuroscience community (see, for example, Adamantidis et al., 2009; Han et al., 2009). A major advantage of ChR2 is that precise patterns of activation can be delivered cell-type selectively

The Temperature Dependence of Sleep

Mammals have evolved a range of behavioural and neurological mechanisms that coordinate cycles of thermoregulation and sleep. Whether diurnal or nocturnal, sleep onset and a reduction in core temperature occur together. Non-rapid eye movement (NREM) sleep episodes are also accompanied by core and brain cooling. Thermoregulatory behaviours, like nest building and curling up, accompany this circadian temperature decline in preparation for sleeping. This could be a matter of simply comfort as animals seek warmth to compensate for lower temperatures. However, in both humans and other mammals, direct skin warming can shorten sleep-latency and promote NREM sleep. We discuss the evidence that body cooling and sleep are more fundamentally connected and that thermoregulatory behaviours, prior to sleep, form warm microclimates that accelerate NREM directly through neuronal circuits. Paradoxically, this warmth might also induce vasodilation and body cooling. In this way, warmth seeking and nesting behaviour might enhance the circadian cycle by activating specific circuits that link NREM initiation to body cooling. We suggest that these circuits explain why NREM onset is most likely when core temperature is at its steepest rate of decline and why transitions to NREM are accompanied by a decrease in brain temperature. This connection may have implications for energy homeostasis and the function of sleep

Ro 15-4513 Antagonizes Alcohol-Induced Sedation in Mice Through aß¿2-type GABA(A) Receptors

Peer reviewedPublisher PD

Dual-Transmitter Systems Regulating Arousal, Attention, Learning and Memory

An array of neuromodulators, including monoamines and neuropeptides, regulate most behavioural and physiological traits. In the past decade, dramatic progress has been made in mapping neuromodulatory circuits, in analysing circuit dynamics, and interrogating circuit function using pharmacogenetic, optogenetic and imaging methods This review will focus on several distinct neural networks (acetylcholine/GABA/glutamate; histamine/GABA; orexin/glutamate; and relaxin-3/GABA) that originate from neural hubs that regulate wakefulness and related attentional and cognitive processes, and highlight approaches that have identified dual transmitter roles in these behavioural functions. Modulation of these different neural networks might be effective treatments of diseases related to arousal/sleep dysfunction and of cognitive dysfunction in psychiatric and neurodegenerative disorders

Cloning, pharmacological characteristics and expression pattern of the rat GABAA receptor α4 subunit

AbstractA cDNA of rat brain encoding the GABAA receptor α4 subunit has been cloned. Recombinant receptors composed of α4, β2 and γ2 subunits bind with high affinity the GABA agonist [3H]muscimol and the benzodiazepine ‘alcohol antagonist’ [3H]Ro 15-4513, but fail to bind benzodiazepine agonists. The α4 subunit is expressed mainly in the thalamus, as assessed by in situ hybridization histochemistry, and may participate in a major population of thalamic GABAA receptors. The α4 mRNA is found at lower levels in cortex and caudate putamen, and is rare in cerebellum

Increased Motor-Impairing Effects of the Neuroactive Steroid Pregnanolone in Mice with Targeted Inactivation of the GABA(A) Receptor gamma 2 Subunit in the Cerebellum

Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABA(A) receptors. In recombinant receptors and genetic mouse models their actions depend on the alpha, beta, and delta subunits of the receptor, especially on those that form extrasynaptic GABA(A) receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched gamma 2 subunit containing receptors and even on alpha beta binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5 beta-pregnan-3 alpha-ol-20-one is altered in genetically engineered mouse models that have deficient GABA(A) receptor mediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABA(A) receptor gamma 2 subunit gene selectively deleted either in parvalbumin-containing cells (including cerebellar Purkinje cells), cerebellar granule cells, or just in cerebellar Purkinje cells were trained on the accelerated rotating rod and then tested for motor impairment after cumulative intraperitoneal dosing of 5 beta-pregnan-3 alpha-ol-20-one. Motor impairing effects of 5 beta-pregnan-3 alpha-ol-20-one were strongly increased in all three mouse models in which gamma 2 subunit-dependent synaptic GABA(A) responses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABA(A) receptors in Purkinje cells normalized the effect of the steroid. Anxiolytic/explorative effects of the steroid in elevated plus maze and light:dark exploration tests in mice with Purkinje cell gamma 2 subunit inactivation were similar to those in control mice. The results suggest that, when the deletion of gamma 2 subunit has removed synaptic GABA(A) receptors from the specific cerebellar neuronal populations, the effects of neuroactive steroids solely on extrasynaptic alpha beta or alpha beta delta receptors lead to enhanced changes in the cerebellum-generated behavior.Peer reviewe

Tectal-derived interneurons contribute to phasic and tonic inhibition in the visual thalamus

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 GABA(A) receptors. Therefore, by revising the conventional view of thalamic interneuron ontogeny we demonstrate how a previously unappreciated mesencephalic population controls thalamic relay neuron excitability.Peer reviewe