Cerebellar Heterogeneity and Selective vulnerability in Spinocerebellar Ataxia Type 1 (SCA1).

Heterogeneity is one of the key features of the healthy brain and selective vulnerability characterizes many, if not all, neurodegenerative diseases. While cerebellum contains majority of brain cells, neither its heterogeneity nor selective vulnerability in disease are well understood. Here we describe molecular, cellular and functional heterogeneity in the context of healthy cerebellum as well as in cerebellar disease Spinocerebellar Ataxia Type 1 (SCA1).

Pain and Itch Processing in Aged Mice.

Most reports agree that aging negatively impacts pain processing and that the prevalence of chronic pain increases significantly with age. To improve current therapies, it is critical that aged animals be included in preclinical studies. Here we compared sensitivities to pain and itch-provoking stimuli in naïve and injured young and aged mice.

Extracellular Matrix Regulation in Physiology and in Brain Disease.

The extracellular matrix (ECM) surrounds cells in the brain, providing structural and functional support. Emerging studies demonstrate that the ECM plays important roles during development, in the healthy adult brain, and in brain diseases. The aim of this review is to briefly discuss the physiological roles of the ECM and its contribution to the pathogenesis of brain disease, highlighting the gene expression changes, transcriptional factors involved, and a role for microglia in ECM regulation.

BDNF is altered in a brain-region specific manner and rescues deficits in Spinocerebellar Ataxia Type 1.

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, dominantly inherited neurodegenerative disease caused by the expanded polyQ tract in the protein ATAXIN1 (ATXN1) and characterized by progressive motor and cognitive impairments. There are no disease-modifying treatments or cures for SCA1. Brain-derived neurotrophic factor (BDNF) plays important role in cerebellar physiology and has shown therapeutic potential for cerebellar pathology in the transgenic mouse model of SCA1, ATXN1[82Q] line that overexpress mutant ATXN1 under a cerebellar Purkinje-cell-specific promoter.

Single nuclei RNA sequencing investigation of the Purkinje cell and glial changes in the cerebellum of transgenic Spinocerebellar ataxia type 1 mice.

Glial cells constitute half the population of the human brain and are essential for normal brain function. Most, if not all, brain diseases are characterized by reactive gliosis, a process by which glial cells respond and contribute to neuronal pathology. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease characterized by a severe degeneration of cerebellar Purkinje cells (PCs) and cerebellar gliosis.

Spatial and Temporal Diversity of Astrocyte Phenotypes in Spinocerebellar Ataxia Type 1 Mice.

While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a CAG repeat expansion in the gene (). We characterized astrocytes across disease progression in the four clinically relevant brain regions, cerebellum, brainstem, hippocampus, and motor cortex, of mice, a knock-in mouse model of SCA1.

Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice.

Peripheral nerve injury-induced neuropathic pain is a chronic and debilitating condition characterized by mechanical hypersensitivity. We previously identified microglial activation via release of colony-stimulating factor 1 (CSF1) from injured sensory neurons as a mechanism contributing to nerve injury-induced pain. Here, we show that intrathecal administration of CSF1, even in the absence of injury, is sufficient to induce pain behavior, but only in male mice.

Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity.

Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons.

Cerebellar Regional Dissection for Molecular Analysis.

Cerebellum plays an important role in several key functions including control of movement, balance, cognition, reward, and affect. Imaging studies indicate that distinct cerebellar regions contribute to these different functions. Molecular studies examining regional cerebellar differences are lagging as they are mostly done on whole cerebellar extracts thereby masking any distinctions across specific cerebellar regions.

Hippocalcin-like 4, a neural calcium sensor, has a limited contribution to pain and itch processing.

Calcium binding proteins are expressed throughout the central and peripheral nervous system and disruption of their activity has major consequences in a wide array of cellular processes, including transmission of nociceptive signals that are processed at the level of the spinal cord. We previously reported that the calcium binding protein, hippocalcin-like 4 (Hpcal4), is heavily expressed in interneurons of the superficial dorsal horn, and that its expression is significantly downregulated in a TR4 mutant mouse model that exhibits major pain and itch deficits due to loss of a subpopulation of excitatory interneurons. That finding suggested that Hpcal4 may be a contributor to the behavioral phenotype of the TR4 mutant mouse.

Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain.

Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation of macrophages around injured sensory neurons in dorsal root ganglia (DRG). Here we demonstrate a critical contribution of DRG macrophages, but not those at the nerve injury site, to both the initiation and maintenance of the mechanical hypersensitivity that characterizes the neuropathic pain phenotype. In contrast to the reported sexual dimorphism in the microglial contribution to neuropathic pain, depletion of DRG macrophages reduces nerve injury-induced mechanical hypersensitivity and expansion of DRG macrophages in both male and female mice.

Ablation of spinal cord estrogen receptor α-expressing interneurons reduces chemically induced modalities of pain and itch.

Estrogens are presumed to underlie, at least in part, the greater pain sensitivity and chronic pain prevalence that women experience compared to men. Although previous studies revealed populations of estrogen receptor-expressing neurons in primary afferents and in superficial dorsal horn neurons, there is little to no information as to the contribution of these neurons to the generation of acute and chronic pain. Here we molecularly characterized neurons in the mouse superficial spinal cord dorsal horn that express estrogen receptor α (ERα) and explored the behavioral consequences of their ablation.

Primary Afferent-Derived BDNF Contributes Minimally to the Processing of Pain and Itch.

BDNF is a critical contributor to neuronal growth, development, learning, and memory. Although extensively studied in the brain, BDNF is also expressed by primary afferent sensory neurons in the peripheral nervous system. Unfortunately, anatomical and functional studies of primary afferent-derived BDNF have been limited by the availability of appropriate molecular tools.

Pain relief by supraspinal gabapentin requires descending noradrenergic inhibitory controls.

Introduction: Gabapentin regulates pain processing by direct action on primary afferent nociceptors and dorsal horn nociresponsive neurons. Through an action at supraspinal levels, gabapentin also engages descending noradrenergic inhibitory controls that indirectly regulate spinal cord pain processing. Although direct injection of gabapentin into the anterior cingulate cortex provides pain relief independent of descending inhibitory controls, it remains unclear whether that effect is representative of what occurs when gabapentin interacts at multiple brain loci, eg, after intracerebroventricular (i.

Effects of Veliparib on Microglial Activation and Functional Outcomes after Traumatic Brain Injury in the Rat and Pig.

The inflammation response induced by brain trauma can impair recovery. This response requires several hours to develop fully and thus provides a clinically relevant therapeutic window of opportunity. Poly(ADP-ribose) polymerase inhibitors suppress inflammatory responses, including brain microglial activation.

Functional Synaptic Integration of Forebrain GABAergic Precursors into the Adult Spinal Cord.

Unlabelled: Spinal cord transplants of embryonic cortical GABAergic progenitor cells derived from the medial ganglionic eminence (MGE) can reverse mechanical hypersensitivity in the mouse models of peripheral nerve injury- and paclitaxel-induced neuropathic pain. Here, we used electrophysiology, immunohistochemistry, and electron microscopy to examine the extent to which MGE cells integrate into host circuitry and recapitulate endogenous inhibitory circuits. Whether the transplants were performed before or after nerve injury, the MGE cells developed into mature neurons and exhibited firing patterns characteristic of subpopulations of cortical and spinal cord inhibitory interneurons.

Aromatase inhibitors and mood disturbances.

We describe the case of a 56-year old woman with no prior psychiatric history who was diagnosed with hormone receptor positive early-stage breast cancer and who developed severe mood changes after administration of anastrozole, which resolved after discontinuation of treatment. Aromatase inhibitors (AIs) are the preferred hormonal approach for postmenopausal women with estrogen hormone sensitive breast cancer. The third-generation agents (anastrozole, letrozole, and exemestane) have been shown to be more effective and safer than the selective estrogen receptor modulators tamoxifen and raloxifen.