M2 receptors are required for spatiotemporal sequence learning in mouse primary visual cortex.

Acetylcholine is a neurotransmitter that plays a variety of roles in the central nervous system. It was previously shown that blocking muscarinic receptors with a nonselective antagonist prevents a form of experience-dependent plasticity termed "spatiotemporal sequence learning" in the mouse primary visual cortex (V1). Muscarinic signaling is a complex process involving the combined activities of five different G protein-coupled receptors, M1-M5, all of which are expressed in the murine brain but differ from each other functionally and in anatomical localization. Here we present electrophysiological evidence that M2, but not M1, receptors are required for spatiotemporal sequence learning in mouse V1. We show in male mice that M2 is highly expressed in the neuropil in V1, especially in thalamorecipient layer 4, and colocalizes with the soma in a subset of somatostatin-expressing neurons in deep layers. We also show that expression of M2 receptors is higher in the monocular region of V1 than it is in the binocular region but that the amount of experience-dependent sequence potentiation is similar in both regions and that blocking muscarinic signaling after visual stimulation does not prevent plasticity. This work establishes a new functional role for M2-type receptors in processing temporal information and demonstrates that monocular circuits are modified by experience in a manner similar to binocular circuits.NEW & NOTEWORTHY Muscarinic acetylcholine receptors are required for multiple forms of plasticity in the brain and support perceptual functions, but the precise role of the five subtypes (M1-M5) are unclear. Here we show that the M2 receptor is specifically required to encode experience-dependent representations of spatiotemporal relationships in both monocular and binocular regions of mouse V1. This work identifies a novel functional role for M2 receptors in coding temporal information into cortical circuits.

Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD.

Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations1-3. In autism spectrum disorder (ASD), this molecular pathology involves the upregulation of microglial, astrocyte and neural-immune genes, the downregulation of synaptic genes, and attenuation of gene-expression gradients in cortex1,2,4-6. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. We find widespread transcriptomic changes across the cortex in ASD, exhibiting an anterior-to-posterior gradient, with the greatest differences in primary visual cortex, coincident with an attenuation of the typical transcriptomic differences between cortical regions. Single-nucleus RNA-sequencing and methylation profiling demonstrate that this robust molecular signature reflects changes in cell-type-specific gene expression, particularly affecting excitatory neurons and glia. Both rare and common ASD-associated genetic variation converge within a downregulated co-expression module involving synaptic signalling, and common variation alone is enriched within a module of upregulated protein chaperone genes. These results highlight widespread molecular changes across the cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions.

Chronic Monocular Deprivation Reveals MMP9-Dependent and -Independent Aspects of Murine Visual System Plasticity.

The deletion of matrix metalloproteinase MMP9 is combined here with chronic monocular deprivation (cMD) to identify the contributions of this proteinase to plasticity in the visual system. Calcium imaging of supragranular neurons of the binocular region of primary visual cortex (V1b) of wild-type mice revealed that cMD initiated at eye opening significantly decreased the strength of deprived-eye visual responses to all stimulus contrasts and spatial frequencies. cMD did not change the selectivity of V1b neurons for the spatial frequency, but orientation selectivity was higher in low spatial frequency-tuned neurons, and orientation and direction selectivity were lower in high spatial frequency-tuned neurons. Constitutive deletion of MMP9 did not impact the stimulus selectivity of V1b neurons, including ocular preference and tuning for spatial frequency, orientation, and direction. However, MMP9-/- mice were completely insensitive to plasticity engaged by cMD, such that the strength of the visual responses evoked by deprived-eye stimulation was maintained across all stimulus contrasts, orientations, directions, and spatial frequencies. Other forms of experience-dependent plasticity, including stimulus selective response potentiation, were normal in MMP9-/- mice. Thus, MMP9 activity is dispensable for many forms of activity-dependent plasticity in the mouse visual system, but is obligatory for the plasticity engaged by cMD.

Remodeling of lateral geniculate nucleus projections to extrastriate area MT following long-term lesions of striate cortex.

Here, we report on a previously unknown form of thalamocortical plasticity observed following lesions of the primary visual area (V1) in marmoset monkeys. In primates, lateral geniculate nucleus (LGN) neurons form parallel pathways to the cortex, which are characterized by the expression of different calcium-binding proteins. LGN projections to the middle temporal (MT) area only originate in the koniocellular layers, where many neurons express calbindin. In contrast, projections to V1 also originate in the magnocellular and parvocellular layers, where neurons express parvalbumin but not calbindin. Our results demonstrate that this specificity is disrupted following long-term (1 to 3 y) unilateral V1 lesions, indicating active rearrangement of the geniculocortical circuit. In lesioned animals, retrograde tracing revealed MT-projecting neurons scattered throughout the lesion projection zone (LPZ, the sector of the LGN that underwent retrograde degeneration following a V1 lesion). Many of the MT-projecting neurons had large cell bodies and were located outside the koniocellular layers. Furthermore, we found that a large percentage of magno- and parvocellular neurons expressed calbindin in addition to the expected parvalbumin expression and that this coexpression was present in many of the MT-projecting neurons within the LPZ. These results demonstrate that V1 lesions trigger neurochemical and structural remodeling of the geniculo-extrastriate pathway, leading to the emergence of nonkoniocellular input to MT. This has potential implications for our understanding of the neurobiological bases of the residual visual abilities that survive V1 lesions, including motion perception and blindsight, and reveals targets for rehabilitation strategies to ameliorate the consequences of cortical blindness.

Proton magnetic resonance spectroscopy in frontotemporal lobar degeneration-related syndromes.

There is an urgent need for a better understanding of the pathophysiology of cognitive impairment in syndromes associated with frontotemporal lobar degeneration. Here, we used magnetic resonance spectroscopy to quantify metabolite deficits in sixty patients with a clinical syndrome associated with frontotemporal lobar degeneration (behavioral variant frontotemporal dementia n = 11, progressive supranuclear palsy n = 26, corticobasal syndrome n = 11, primary progressive aphasias n = 12), and 38 age- and sex-matched healthy controls. We measured nine metabolites in the right inferior frontal gyrus, superior temporal gyrus and right primary visual cortex. Metabolite concentrations were corrected for age, sex, and partial volume then compared with cognitive and behavioral measures using canonical correlation analysis. Metabolite concentrations varied significantly by brain region and diagnosis (region x metabolite x diagnosis interaction F(64) = 1.73, p < 0.001, corrected for age, sex, and atrophy within the voxel). N-acetyl aspartate and glutamate concentrations were reduced in the right prefrontal cortex in behavioral variant frontotemporal dementia and progressive supranuclear palsy, even after partial volume correction. The reduction of these metabolites was associated with executive dysfunction and behavioral impairment (canonical correlation analysis R = 0.85, p < 0.001).

Revealing nonlinear neural decoding by analyzing choices.

Sensory data about most natural task-relevant variables are entangled with task-irrelevant nuisance variables. The neurons that encode these relevant signals typically constitute a nonlinear population code. Here we present a theoretical framework for quantifying how the brain uses or decodes its nonlinear information. Our theory obeys fundamental mathematical limitations on information content inherited from the sensory periphery, describing redundant codes when there are many more cortical neurons than primary sensory neurons. The theory predicts that if the brain uses its nonlinear population codes optimally, then more informative patterns should be more correlated with choices. More specifically, the theory predicts a simple, easily computed quantitative relationship between fluctuating neural activity and behavioral choices that reveals the decoding efficiency. This relationship holds for optimal feedforward networks of modest complexity, when experiments are performed under natural nuisance variation. We analyze recordings from primary visual cortex of monkeys discriminating the distribution from which oriented stimuli were drawn, and find these data are consistent with the hypothesis of near-optimal nonlinear decoding.

Caffeine abrogates oxidative stress imbalance: Its implication on lateral geniculate nucleus and visual cortex following hyaluronic acid exposure.

This study assessed the role of caffeine (adenosine receptor antagonist) in the Lateral geniculate body as well as the primary visual cortex of hyaluronic acid model of glaucomatous rats. Twenty (20) male Long evans rats were randomly divided into four groups with five animals each. This research confirmed that hyaluronic acid (HA) significantly induces elevated intraocular pressure from 18 to 35 mmHg and caffeine had no effect on its reduction to palliate visual impairment; There were a significant increase in the lipid peroxidation and conversely decrease in superoxide level with HA which were attenuated by caffeine. Although, caffeine showed a capability of ameliorating the histopathological changes induced by HA in terms of maintenance of a viable neuronal cell count and significant reduction of tumour necrosis factor-α immune positive cells in the LGB and visual cortex. These findings suggest that caffeine was unable to lower the intraocular pressure after hyaluronic acid exposure but has the ability to restore the antioxidant imbalance via mitigating pro-oxidant mediators and abrogate neurodegeneration.

Neural response during temporal - and spatial luminance contrast processing and its manifestation in the blood-oxygen-level-dependent-signal in striate and extra-striate cortex.

The primate visual system has been the prime site for investigating the relationship between stimulus property, neural response and blood-oxygen-level-dependent (BOLD)-signal; yet this relationship remains ill-understood. Electrophysiological studies have shown that the ability to visualise a neural response is determined by stimulus property and presentation paradigm. The neural response in the human visual cortex consists of a phasic response processing temporal and tonic response processing spatial luminance contrast. We investigated their influence on the BOLD signal from the visual cortex. To do so, we compared BOLD signal amplitude from BA17 and BA18 of 15 human volunteers to visual patterns varying the size of the active neural population and the discharge activity of this population. The BOLD signal amplitude in both areas reflected the discharge activity of the active neural population but not the size of the active neural population. For identical stimuli, BOLD signal amplitude in BA17 exceeded than that of BA18. This indicates that the BOLD signal reflects the tonic neural neuronal response during spatial luminance contrast processing. The difference in BOLD signal amplitude between BA17 and BA18 is accounted for by differences in neurophysiological and cytoarchitectonic differences between the two areas. Our findings offer an understanding of the relationship between stimulus property, neural response and the BOLD signal by considering the cytoarchitectonic, and neurophysiological make-up between different cortical areas and the influence of a phasic and tonic neural response on local deoxyhaemoglobin concentration. Conversely, differences in BOLD signal between brain structures and stimuli provide cues to the influence of different neurophysiological mechanisms on the neural response.

Defining early changes in Alzheimer's disease from RNA sequencing of brain regions differentially affected by pathology.

Tau pathology in Alzheimer's disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The 'early' AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.

Sinoatrial node pacemaker cells share dominant biological properties with glutamatergic neurons.

Activation of the heart normally begins in the sinoatrial node (SAN). Electrical impulses spontaneously released by SAN pacemaker cells (SANPCs) trigger the contraction of the heart. However, the cellular nature of SANPCs remains controversial. Here, we report that SANPCs exhibit glutamatergic neuron-like properties. By comparing the single-cell transcriptome of SANPCs with that of cells from primary visual cortex in mouse, we found that SANPCs co-clustered with cortical neurons. Tissue and cellular imaging confirmed that SANPCs contained key elements of glutamatergic neurotransmitter system, expressing genes encoding glutamate synthesis pathway (Gls), ionotropic and metabotropic glutamate receptors (Grina, Gria3, Grm1 and Grm5), and glutamate transporters (Slc17a7). SANPCs highly expressed cell markers of glutamatergic neurons (Snap25 and Slc17a7), whereas Gad1, a marker of GABAergic neurons, was negative. Functional studies revealed that inhibition of glutamate receptors or transporters reduced spontaneous pacing frequency of isolated SAN tissues and spontaneous Ca2+ transients frequency in single SANPC. Collectively, our work suggests that SANPCs share dominant biological properties with glutamatergic neurons, and the glutamatergic neurotransmitter system may act as an intrinsic regulation module of heart rhythm, which provides a potential intervention target for pacemaker cell-associated arrhythmias.