Non-uniform distribution of dendritic nonlinearities differentially engages thalamostriatal and corticostriatal inputs onto cholinergic interneurons

The tonic activity of striatal cholinergic interneurons (CINs) is modified differentially by their afferent inputs. Although their unitary synaptic currents are identical, cortical inputs onto distal dendrites only weakly entrain CINs, whereas proximal thalamic inputs trigger abrupt pauses in discharge in response to salient external stimuli. To test whether the dendritic expression of the active conductances that drive autonomous discharge contribute to the CINs' capacity to dissociate cortical from thalamic inputs, we used an optogenetics-based method to quantify dendritic excitability. We found that the persistent sodium (NaP) current gave rise to dendritic boosting and that the hyperpolarization-activated cyclic nucleotide-gated (HCN) current gave rise to a subhertz membrane resonance. This resonance may underlie our novel finding of an association between CIN pauses and internally-generated slow wave events in sleeping non-human primates. Moreover, our method indicated that dendritic NaP and HCN currents were preferentially expressed in proximal dendrites. We validated this non-uniform distribution with two-photon imaging of dendritic back-propagating action potentials, and by demonstrating boosting of thalamic, but not cortical, inputs by NaP currents. Thus, the localization of active dendritic conductances in CIN dendrites mirrors the spatial distribution of afferent terminals and may promote their differential responses to thalamic vs. cortical inputs.

Knismesis: the aversive facet of tickle

There are two different kinds of tickle, knismesis (feather-light tickle) and gargalesis (more intense tickle eliciting involuntary laughter). In this article we review earlier and recent advances in tickle psychophysics and in neurophysiology of touch afferents and hypothesize that knismesis is signaled by populations of rapidly adapted hair follicle afferents, can stimulate itch neurons via dorsal horn projections, and is heavily moderated by afferent inputs from other touch neurons. Finally, we suggest that pathological light touch intolerance observed in autism spectrum disorder may reflect knismesis hyper-responsiveness and attenuated knismesis inhibition stemming from impaired integration of sensory inputs from other touch submodalities.

Endocannabinoid Modulation of Nucleus Accumbens Microcircuitry and Terminal Dopamine Release

The nucleus accumbens (NAc) is located in the ventromedial portion of the striatum and is vital to valence-based predictions and motivated action. The neural architecture of the NAc allows for complex interactions between various cell types that filter incoming and outgoing information. Dopamine (DA) input serves a crucial role in modulating NAc function, but the mechanisms that control terminal DA release and its effect on NAc neurons continues to be elucidated. The endocannabinoid (eCB) system has emerged as an important filter of neural circuitry within the NAc that locally shapes terminal DA release through various cell type- and site-specific actions. Here, we will discuss how eCB signaling modulates terminal DA release by shaping the activity patterns of NAc neurons and their afferent inputs. We then discuss recent technological advancements that are capable of dissecting how distinct cell types, their afferent projections, and local neuromodulators influence valence-based actions.

Widely Different Correlation Patterns Between Pairs of Adjacent Thalamic Neurons In vivo

We have previously reported different spike firing correlation patterns among pairs of adjacent pyramidal neurons within the same layer of S1 cortex in vivo, which was argued to suggest that acquired synaptic weight modifications would tend to differentiate adjacent cortical neurons despite them having access to near-identical afferent inputs. Here we made simultaneous single-electrode loose patch-clamp recordings from 14 pairs of adjacent neurons in the lateral thalamus of the ketamine-xylazine anesthetized rat in vivo to study the correlation patterns in their spike firing. As the synapses on thalamic neurons are dominated by a high number of low weight cortical inputs, which would be expected to be shared for two adjacent neurons, and as far as thalamic neurons have homogenous membrane physiology and spike generation, they would be expected to have overall similar spike firing and therefore also correlation patterns. However, we find that across a variety of thalamic nuclei the correlation patterns between pairs of adjacent thalamic neurons vary widely. The findings suggest that the connectivity and cellular physiology of the thalamocortical circuitry, in contrast to what would be expected from a straightforward interpretation of corticothalamic maps and uniform intrinsic cellular neurophysiology, has been shaped by learning to the extent that each pair of thalamic neuron has a unique relationship in their spike firing activity.

066 Noradrenaline and acetylcholine inhibit sleep-promoting neurons of ventrolateral preoptic area through a local GABAergic circuit

Introduction The ventrolateral preoptic (VLPO) nucleus is a key area involved in the initiation and maintenance of sleep. During wakefulness, sleep-promoting galanin neurons in the VLPO are directly inhibited by arousal signals including noradrenaline and acetylcholine. We have found that while these neurotransmitters directly inhibit VLPO galanin neurons, they also activate GABAergic neurons in the VLPO that do not express galanin. We propose that when activated by monoaminergic and cholinergic inputs, these local VLPO GABAergic neurons provide an additional inhibition of the VLPO galanin sleep-promoting neurons. We tested this model in brain slices in mice. Methods We studied VLPO galanin neurons in mouse brain slices using patch-clamp recordings. We recorded from fluorescently labeled VLPO galanin neurons following the injection of a cre-dependent AAV encoding for mCherry, into the VLPO of Gal-cre mice. For the optogenetic studies we expressed channelrhodopsin-2 (ChR-2) in VLPO VGAT neurons and mCherry in galanin neurons by injecting a flp-dependent and a cre-dependent AAV encoding respectively for ChR2 and mCherry into the VLPO of VGAT-flp::Gal-cre mice. We photo-stimulated local GABAergic neurons and recorded from labeled VLPO galanin neurons. Noradrenaline, carbachol and receptor antagonists were bath-applied. Results Noradrenaline and carbachol inhibited VLPO galanin neurons by alpha-2 and muscarinic receptors and these effects were maintained in the presence of tetrodotoxin (TTX) indicating, as previously proposed, a direct inhibitory effect of noradrenaline and carbachol on VLPO galanin neurons. In addition, both noradrenaline and carbachol increased the frequency of spontaneous inhibitory post-synaptic currents (sIPSCs) of VLPO galanin neurons, suggesting an additional inhibitory action on VLPO galanin neurons. Finally, optogenetic stimulation of local VLPO GABAergic neurons produced short latency, TTX-resistant, opto-evoked IPSCs in VLPO galanin neurons. Both noradrenaline and carbachol increased the amplitude of these opto-evoked IPSCs by the activation of alpha-1 and muscarinic receptors. Conclusion Our results demonstrate that noradrenaline and acetylcholine inhibit VLPO galanin neurons directly and indirectly. Both noradrenaline and acetylcholine increase GABAergic afferent inputs to VLPO galanin neurons by activating local GABAergic neurons. We propose that during wakefulness this feedforward inhibition provides additional inhibition of VLPO galanin sleep-promoting neurons. Support (if any) NS091126 and HL149630

Neuropathic corneal pain and dry eye: a continuum of nociception

Throughout the body, damage to peripheral nerves normally involved in nociception may produce a constellation of symptoms—including irritation, itchiness and pain. The neurobiological processes involved in corneal symptoms of dry eye (DE) and neuropathic corneal pain (NCP) have not been clearly considered in terms of nociceptive processing. The conventional underlying presumption is that a labelled line principle is responsible; that these distinct perceptions are hard coded by primary afferent inputs to the central nervous system. This presumption oversimplifies the neurobiological mechanisms underlying somatosensory perception. The labelled line perspective that DE represents a chronic pain condition does not make intuitive sense: how can an eye condition that is not painful in most cases be considered a pain condition? Does not chronic pain by definition require pain to be present? On the other hand, NCP, a term that clearly denotes a painful condition, has historically seemed to resonate with clinical significance. Both DE and NCP can share similar features, yet their differentiation is not always clear. As is often the case, clinical terms arise from different disciplines, with DE evolving from ophthalmological findings and NCP inspired by pain neurophysiology. This review evaluates the current definition of these terms, the rationale for their overlap and how the neurophysiology of itch impacts our understanding of these conditions as a continuum of the same disease. Despite the complexity of nociceptive physiology, an understanding of these mechanisms will allow us a more precise therapeutic approach.

Plasticity in Prefrontal Cortex Induced by Coordinated Synaptic Transmission Arising from Reuniens/Rhomboid Nuclei and Hippocampus

The nucleus reuniens and rhomboid nuclei of the thalamus (ReRh) are reciprocally connected to a range of higher order cortices including hippocampus (HPC) and medial prefrontal cortex (mPFC). The physiological function of ReRh is well predicted by requirement for interactions between mPFC and HPC, including associative recognition memory, spatial navigation and working memory. Although anatomical and electrophysiological evidence suggests ReRh makes excitatory synapses in mPFC there is little data on the physiological properties of these projections, or whether ReRh and HPC target overlapping cell populations and, if so, how they interact. We demonstrate in ex vivo mPFC slices that ReRh and HPC afferent inputs converge onto more than two-thirds of layer 5 pyramidal neurons, show that ReRh, but not HPC, undergoes marked short-term plasticity during theta frequency transmission, and that HPC, but not ReRh, afferents are subject to neuromodulation by acetylcholine acting via muscarinic receptor M2. Finally, we demonstrate that pairing HPC followed by ReRh (but not pairing ReRh followed by HPC) at theta frequency induces associative, NMDA receptor dependent synaptic plasticity in both inputs to mPFC. These data provide vital physiological phenotypes of the synapses of this circuit and provide a novel mechanism for HPC-ReRh-mPFC encoding.

Dopamine Cell Therapy: From Cell Replacement to Circuitry Repair

Cell therapy for Parkinson’s disease (PD) is aimed to replace the degenerated midbrain dopamine (mDA) neurons and restore DA neurotransmission in the denervated forebrain targets. A limitation of the intrastriatal grafting approach, which is currently used in clinical trials, is that the mDA neurons are implanted into the target area, in most cases the putamen, and not in the ventral midbrain where they normally reside. This ectopic location of the cells may limit their functionality due to the lack of appropriate afferent regulation from the host. Homotopic transplantation, into the substantia nigra, is now being pursued in rodent PD models as a way to achieve more complete circuitry repair. Intranigral grafts of mDA neurons, derived from human embryonic stem cells, have the capacity to re-establish the nigrostriatal and mesolimbic pathways in their entirety and restore dense functional innervations in striatal, limbic and cortical areas. Tracing of host afferent inputs using the rabies tracing technique shows that the afferent connectivity of grafts implanted in the nigra matches closely that of the intrinsic mDA system, suggesting a degree of circuitry reconstruction that exceeds what has been achieved before. This approach holds great promise, but to match the larger size of the human brain, and the 10 times greater distance between substantia nigra and its forebrain targets, it may be necessary to find ways to improve the growth capacity of the grafted mDA neurons, pointing to a combined approach where growth promoting factors are used to enhance the performance of mDA neuron grafts.

The path from trigeminal asymmetry to cognitive impairment: a behavioral and molecular study

Trigeminal input exerts acute and chronic effects on the brain, modulating cognitive functions. Here, new data from humans and animals suggest that these effects are caused by trigeminal influences on the Locus Coeruleus (LC). In humans subjects clenching with masseter asymmetric activity, occlusal correction improved cognition, alongside with reductions in pupil size and anisocoria, proxies of LC activity and asymmetry, respectively. Notably, reductions in pupil size at rest on the hypertonic side predicted cognitive improvements. In adult rats, a distal unilateral section of the trigeminal mandibular branch reduced, on the contralateral side, the expression of c-Fos (brainstem) and BDNF (brainstem, hippocampus, frontal cortex). This counterintuitive finding can be explained by the following model: teeth contact perception loss on the lesioned side results in an increased occlusal effort, which enhances afferent inputs from muscle spindles and posterior periodontal receptors, spared by the distal lesion. Such effort leads to a reduced engagement of the intact side, with a corresponding reduction in the afferent inputs to the LC and in c-Fos and BDNF gene expression. In conclusion, acute effects of malocclusion on performance seem mediated by the LC, which could also contribute to the chronic trophic dysfunction induced by loss of trigeminal input.

Early Lipid Raft-Related Changes: Interplay between Unilateral Denervation and Hindlimb Suspension

Muscle disuse and denervation leads to muscle atrophy, but underlying mechanisms can be different. Previously, we have found ceramide (Cer) accumulation and lipid raft disruption after acute hindlimb suspension (HS), a model of muscle disuse. Herein, using biochemical and fluorescent approaches the influence of unilateral denervation itself and in combination with short-term HS on membrane-related parameters of rat soleus muscle was studied. Denervation increased immunoexpression of sphingomyelinase and Cer in plasmalemmal regions, but decreased Cer content in the raft fraction and enhanced lipid raft integrity. Preliminary denervation suppressed (1) HS-induced Cer accumulation in plasmalemmal regions, shown for both nonraft and raft-fractions; (2) HS-mediated decrease in lipid raft integrity. Similar to denervation, inhibition of the sciatic nerve afferents with capsaicin itself increased Cer plasmalemmal immunoexpression, but attenuated the membrane-related effects of HS. Finally, both denervation and capsaicin treatment increased immunoexpression of proapoptotic protein Bax and inhibited HS-driven increase in antiapoptotic protein Bcl-2. Thus, denervation can increase lipid raft formation and attenuate HS-induced alterations probably due to decrease of Cer levels in the raft fraction. The effects of denervation could be at least partially caused by the loss of afferentation. The study points to the importance of motor and afferent inputs in control of Cer distribution and thereby stability of lipid rafts in the junctional and extrajunctional membranes of the muscle.