Visual Deprivation Selectively Reduces Thalamic Reticular Nucleus-Mediated Inhibition of the Auditory Thalamus in Adults.

Sensory loss leads to widespread cross-modal plasticity across brain areas to allow the remaining senses to guide behavior. While multimodal sensory interactions are often attributed to higher-order sensory areas, cross-modal plasticity has been observed at the level of synaptic changes even across primary sensory cortices. In particular, vision loss leads to widespread circuit adaptation in the primary auditory cortex (A1) even in adults. Here we report using mice of both sexes in which cross-modal plasticity occurs even earlier in the sensory-processing pathway at the level of the thalamus in a modality-selective manner. A week of visual deprivation reduced inhibitory synaptic transmission from the thalamic reticular nucleus (TRN) to the primary auditory thalamus (MGBv) without changes to the primary visual thalamus (dLGN). The plasticity of TRN inhibition to MGBv was observed as a reduction in postsynaptic gain and short-term depression. There was no observable plasticity of the cortical feedback excitatory synaptic transmission from the primary visual cortex to dLGN or TRN and A1 to MGBv, which suggests that the visual deprivation-induced plasticity occurs predominantly at the level of thalamic inhibition. We provide evidence that visual deprivation-induced change in the short-term depression of TRN inhibition to MGBv involves endocannabinoid CB1 receptors. TRN inhibition is considered critical for sensory gating, selective attention, and multimodal performances; hence, its plasticity has implications for sensory processing. Our results suggest that selective disinhibition and altered short-term dynamics of TRN inhibition in the spared thalamic nucleus support cross-modal plasticity in the adult brain.SIGNIFICANCE STATEMENT Losing vision triggers adaptation of the brain to enhance the processing of the remaining senses, which can be observed as better auditory performance in blind subjects. We previously found that depriving vision of adult rodents produces widespread circuit reorganization in the primary auditory cortex and enhances auditory processing at a neural level. Here we report that visual deprivation-induced plasticity in adults occurs much earlier in the auditory pathway, at the level of thalamic inhibition. Sensory processing is largely gated at the level of the thalamus via strong cortical feedback inhibition mediated through the thalamic reticular nucleus (TRN). We found that TRN inhibition of the auditory thalamus is selectively reduced by visual deprivation, thus playing a role in adult cross-modal plasticity.

Disrupted AMPA Receptor Function upon Genetic- or Antibody-Mediated Loss of Autism-Associated CASPR2.

Neuropsychiatric disorders share susceptibility genes, suggesting a common origin. One such gene is CNTNAP2 encoding contactin-associated protein 2 (CASPR2), which harbours mutations associated to autism, schizophrenia, and intellectual disability. Antibodies targeting CASPR2 have also been recently described in patients with several neurological disorders, such as neuromyotonia, Morvan's syndrome, and limbic encephalitis. Despite the clear implication of CNTNAP2 and CASPR2 in neuropsychiatric disorders, the pathogenic mechanisms associated with alterations in CASPR2 function are unknown. Here, we show that Caspr2 is expressed in excitatory synapses in the cortex, and that silencing its expression in vitro or in vivo decreases the synaptic expression of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and the amplitude of AMPA receptor-mediated currents. Furthermore, Caspr2 loss of function blocks synaptic scaling in vitro and experience-dependent homoeostatic synaptic plasticity in the visual cortex. Patient CASPR2 antibodies decrease the dendritic levels of Caspr2 and synaptic AMPA receptor trafficking, and perturb excitatory transmission in the visual cortex. These results suggest that mutations in CNTNAP2 may contribute to alterations in AMPA receptor function and homoeostatic plasticity, and indicate that antibodies from anti-CASPR2 encephalitis patients affect cortical excitatory transmission.

Experience-dependent homeostasis of 'noise' at inhibitory synapses preserves information coding in adult visual cortex.

Synapses are intrinsically 'noisy' in that neurotransmitter is occasionally released in the absence of an action potential. At inhibitory synapses, the frequency of action potential-independent release is orders of magnitude higher than that at excitatory synapses raising speculations that it may serve a function. Here we report that the frequency of action potential-independent inhibitory synaptic 'noise' (i.e. miniature inhibitory postsynaptic currents, mIPSCs) is highly regulated by sensory experience in visual cortex. Importantly, regulation of mIPSC frequency is so far the predominant form of functional plasticity at inhibitory synapses in adults during the refractory period for plasticity and is a locus of rapid non-genomic actions of oestrogen. Models predict that regulating the frequency of mIPSCs, together with the previously characterized synaptic scaling of miniature excitatory PSCs, allows homeostatic maintenance of both the mean and variance of inputs to a neuron, a necessary feature of probabilistic population codes. Furthermore, mIPSC frequency regulation allows preservation of the temporal profile of neural responses while homeostatically regulating the overall firing rate. Our results suggest that the control of inhibitory 'noise' allows adaptive maintenance of adult cortical function in tune with the sensory environment.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'.

An Integrative Approach to STEM Concepts in an Introductory Neuroscience Course: Gains in Interdisciplinary Awareness.

Neuroscience is an integrative discipline for which students must achieve broad-based proficiency in many of the sciences. We are motivated by the premise that student pursuit of proficiency in science, technology, engineering, and mathematics (STEM) can be supported by awareness of the application of knowledge and tools from the various disciplines for solving complex problems. We refer to this awareness as "interdisciplinary awareness." Faculty from biology, chemistry, mathematics/computer science, physics, and psychology departments contributed to a novel integrative introductory neuroscience course with no pre-requisites. STEM concepts were taught in "flipped" class modules throughout the semester: Students viewed brief videos and completed accompanying homework assignments independently. In subsequent class meetings, students applied the STEM concepts to understand nervous system structure and function through engaged learning activities. The integrative introduction to neuroscience course was compared to two other courses to test the hypothesis that it would lead to greater gains in interdisciplinary awareness than courses that overlap in content but were not designed for this specific goal. Data on interdisciplinary awareness were collected using previously published tools at the beginning and end of each course, enabling within-subject analyses. Students in the integrative course significantly increased their identification of scientific terms as relevant to neuroscience in a term-discipline relevance survey and increased their use of terms related to levels of analysis (e.g., molecular, cellular, systems) in response to an open-ended prompt. These gains were seen over time within the integrative introduction to neuroscience course as well as relative to the other two courses.

Cross-modal synaptic plasticity in adult primary sensory cortices.

Sensory loss leads to widespread adaptation of brain circuits to allow an organism to navigate its environment with its remaining senses, which is broadly referred to as cross-modal plasticity. Such adaptation can be observed even in the primary sensory cortices, and falls into two distinct categories: recruitment of the deprived sensory cortex for processing the remaining senses, which we term 'cross-modal recruitment', and experience-dependent refinement of the spared sensory cortices referred to as 'compensatory plasticity.' Here we will review recent studies demonstrating that cortical adaptation to sensory loss involves LTP/LTD and homeostatic synaptic plasticity. Cross-modal synaptic plasticity is observed in adults, hence cross-modal sensory deprivation may be an effective way to promote plasticity in adult primary sensory cortices.

Experience-dependent homeostatic synaptic plasticity in neocortex.

The organism's ability to adapt to the changing sensory environment is due in part to the ability of the nervous system to change with experience. Input and synapse specific Hebbian plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), are critical for sculpting the nervous system to wire its circuit in tune with the environment and for storing memories. However, these synaptic plasticity mechanisms are innately unstable and require another mode of plasticity that maintains homeostasis to allow neurons to function within a desired dynamic range. Several modes of homeostatic adaptation are known, some of which work at the synaptic level. This review will focus on the known mechanisms of experience-induced homeostatic synaptic plasticity in the neocortex and their potential function in sensory cortex plasticity. This article is part of the Special Issue entitled 'Homeostatic Synaptic Plasticity'.

Pathological activity in mediodorsal thalamus of rats with spinal cord injury pain.

Spinal cord injury (SCI) results not only in motor deficits, but produces, in many patients, excruciating chronic pain (SCI pain). We have previously shown, in a rodent model, that SCI causes suppression of activity in the GABAergic nucleus, the zona incerta (ZI), and concomitant increased activity in one of its main targets, the posterior nucleus of the thalamus (PO); the increased PO activity is correlated with the maintenance and expression of hyperalgesia after SCI. Here, we test the hypothesis that SCI causes a similar pathological increase in other thalamic nuclei regulated by the ZI, specifically the mediodorsal thalamus (MD), which is involved in the emotional-affective aspects of pain. We recorded single and multiunit activity from MD of either anesthetized or awake rats, and compared data from rats with SCI with data from sham-operated controls (anesthetized experiments) or with data from the same animals prelesion (awake experiments). Consistent with our hypothesis, MD neurons from rats with SCI show significant increases in spontaneous firing rates and in the magnitude and duration of responses to noxious stimuli. In a subset of anesthetized animals, similar changes in activity of MD neurons were produced by pharmacologically inactivating ZI in naive rats, suggesting that the changes in the MD after SCI are related to suppressed inhibition from the ZI. These data support our hypothesis that SCI pain results, at least in part, from a loss of inhibition to thalamic nuclei associated with both the sensory-discriminative and emotional-affective components of pain.