Microglia, brain-resident innate immune cells, have been extensively studied in neurodegenerative contexts like Alzheimer's disease. The Coronavirus disease 2019 (COVID-19) pandemic highlighted how peripheral infection and inflammation can be detrimental to the neuroimmune milieu and initiate microgliosis driven by peripheral inflammation. Microglia can remain deleterious to brain health by sustaining inflammation in the central nervous system even after the clearance of the original immunogenic agents. In this chapter, we discuss how pulmonary infection with Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) can lead to neurovascular and neuroimmune inflammation causing the neurological syndrome of post-acute sequelae of COVID-19 (PASC). Further, we incorporate lessons from the Human Immunodeficiency Virus' (HIV's) effects on microglial functioning in the era of combined antiretroviral therapies (cART) that contribute to HIV-1 associated neurocognitive disorders (HAND). Finally, we describe roles for mixed lineage kinase 3 (MLK3) and leucine-rich repeat kinase (LRRK2) as key regulators of multiple inflammatory and apoptotic pathways important to the pathogenesis of PASC and HAND. Inhibition of these pathways provides a therapeutically synergistic method of treating both PASC and HAND.

Traumatic Brain Injury (TBI) is a significant public health issue, with diverse consequences across the lifespan. This comprehensive review explores the complex interplay between age-related responses and the immune system following TBI. TBI exhibits distinct effects in pediatric, adult, and elderly populations, with profound implications for recovery and long-term outcomes. The immune system, as a key player in the post-TBI inflammatory cascade, exerts age-dependent influences on inflammation, neuroinflammation, and tissue repair. We examine the evolving understanding of age-related neuroinflammatory responses, cytokine profiles, and the role of immune cells, such as microglia and T cells, in the context of TBI. Furthermore, we evaluate the therapeutic implications of age-specific immunomodulation strategies toward mitigating TBI-associated neuropathology. This review consolidates the current knowledge on age-related immune responses in TBI, shedding light on potential avenues for tailored therapeutic interventions across the age spectrum. Understanding these nuanced responses is crucial for optimizing patient care and enhancing recovery outcomes in the aftermath of traumatic brain injury.

The synapse is a highly specialized asymmetric structure that transmits and stores information in the brain. The size of pre- and postsynaptic structures and function is well coordinated at the individual synapse level. For example, large postsynaptic dendritic spines have a larger postsynaptic density with higher α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) number on their surface, while juxtaposing presynaptic terminals have a larger active zone and higher release probability. This indicates that pre- and postsynaptic domains bidirectionally communicate to coordinate assembly of specific molecules on both sides of the synaptic cleft. Cell adhesion molecules (CAMs) that localize at synapses form transsynaptic protein interactions across the synaptic cleft and play important roles in synapse formation and regulation. The extracellular domain of CAMs is essential for specific synapse formation and function. In contrast, the intracellular domain is necessary for binding with synaptic molecules and signal transduction. Therefore, CAMs play an essential role on synapse function and structure. In fact, ample evidence indicates that transsynaptic CAMs instruct and modulate functions at presynaptic sites. This chapter focuses on transsynaptic protein interactions that regulate presynaptic functions emphasizing the role of neuronal CAMs and the intracellular mechanism of their regulation.

To acquire and maintain outstanding sensorimotor skills for playing musical instruments inevitably requires extensive training from childhood. However, on the way toward musical excellence, musicians sometimes develop serious disorders, such as tendinitis, carpal tunnel syndrome, and task-specific focal dystonia. Particularly, task-specific focal dystonia in musicians, which is referred to as musician's dystonia (MD), has no perfect cure and therefore often terminates professional careers of musicians. To better understand its pathological and pathophysiological mechanisms, the present article focuses on malfunctions of the sensorimotor system at the behavioral and neurophysiological levels. Based on emerging empirical evidence, we propose that the aberrant sensorimotor integration, possibly which occurs in both cortical and subcortical systems, underlies not only movement incoordination between the fingers (i.e., maladaptive synergy) but also failure of long-term retention of intervention effects in the patients with MD.

Electromyography (EMG) methods allow quantitative analyses of motor function. The techniques include intramuscular recordings that are performed in vivo. However, recording muscle activity in freely moving mice, particularly in models of motor disease, often creates challenges that prevent the acquisition of clean signals. Recording preparations must be stable enough for the experimenter to collect an adequate number of signals for statistical analyses. Instability results in a low signal-to-noise ratio that prohibits proper isolation of EMG signals from the target muscle during the behavior of interest. Such insufficient isolation prevents the analysis of full electrical potential waveforms. In this case, resolving the shape of a waveform to differentiate individual spikes and bursts of muscle activity can be difficult. A common source of instability is an inadequate surgery. Poor surgical techniques cause blood loss, tissue damage, poor healing, encumbered movement, and unstable implantation of the electrodes. Here, we describe an optimized surgical procedure that ensures electrode stability for in vivo muscle recordings. We implement our technique to obtain recordings from agonist and antagonist muscle pairs in the hindlimbs of freely moving adult mice. We validate the stability of our method by holding EMG recordings during dystonic behavior. Our approach is ideal for studying normal and abnormal motor function in actively behaving mice and valuable for recording intramuscular activity when considerable motion is expected.

Musician's dystonia is often described as a neurological disorder, resulting from reduced inhibition in the basal ganglia and the cerebellum and dysfunctional cortical plasticity. However, several studies over the last decades support the hypothesis that psychological factors play an important role in the aetiology of dystonia, contradicting its classification as "purely neurological". Especially adverse childhood experiences (ACEs) such as neglect, maltreatment, or household dysfunction may influence the sensorimotor system, additionally to the impact they have on psychological traits. They are known to alter limbic networks, such as the amygdala, the hippocampus, and the stress response via the hypothalamus-pituitary-adrenal (HPA) axis and might also affect the cortico-striatal-thalamo-cortical loop that is vital for correct motor movement learning. Especially a higher activity of the basolateral amygdala could be important by increasing the consolidation of dysfunctional motor memories in stressful situations.Therefore, this chapter explores how musician's dystonia might be a result of dysfunctional stress-coping mechanisms, additionally to the already established neurological alterations.

The central nervous system is composed of neural ensembles, and their activity patterns are neural correlates of cognitive functions. Those ensembles are networks of neurons connected to each other by synapses. Most neurons integrate synaptic signal through a remarkable subcellular structure called spine. Dendritic spines are protrusions whose diverse shapes make them appear as a specific neuronal compartment, and they have been the focus of studies for more than a century. Soon after their first description by Ramón y Cajal, it has been hypothesized that spine morphological changes could modify neuronal connectivity and sustain cognitive abilities. Later studies demonstrated that changes in spine density and morphology occurred in experience-dependent plasticity during development, and in clinical cases of mental retardation. This gave ground for the assumption that dendritic spines are the particular locus of cerebral plasticity. With the discovery of synaptic long-term potentiation, a research program emerged with the aim to establish whether dendritic spine plasticity could explain learning and memory. The development of live imaging methods revealed on the one hand that dendritic spine remodeling is compatible with learning process and, on the other hand, that theirlong-term stability is compatible with lifelong memories. Furthermore, the study of the mechanisms of spine growth and maintenance shed new light on the rules of plasticity. In behavioral paradigms of memory, spine formation or elimination and morphological changes were found to correlate with learning. In a last critical step, recent experiments have provided evidence that dendritic spines play a causal role in learning and memory.

Military personnel during combat or peacekeeping operations are exposed to extreme climates of hot or cold environments for longer durations. Spinal cord injury is quite common in military personnel following central nervous system (CNS) trauma indicating a possibility of altered pathophysiological responses at different ambient temperatures. Our previous studies show that the pathophysiology of brain injury is exacerbated in animals acclimated to cold (5°C) or hot (30°C) environments. In these diverse ambient temperature zones, trauma exacerbated oxidative stress generation inducing greater blood-brain barrier (BBB) permeability and cell damage. Extracts of Ginkgo biloba EGb-761 and BN-52021 treatment reduces brain pathology following heat stress. This effect is further improved following TiO2 nanowired delivery in heat stress in animal models. Several studies indicate the role of EGb-761 in attenuating spinal cord induced neuronal damages and improved functional deficit. This is quite likely that these effects are further improved following nanowired delivery of EGb-761 and BN-52021 with cerebrolysin-a balanced composition of several neurotrophic factors and peptide fragments in spinal cord trauma. In this review, TiO2 nanowired delivery of EGb-761 and BN-52021 with nanowired cerebrolysin is examined in a rat model of spinal cord injury at cold environment. Our results show that spinal cord injury aggravates cord pathology in cold-acclimated rats and nanowired delivery of EGb-761 and BN-52021 with cerebrolysin significantly induced superior neuroprotection, not reported earlier.

Sleep deprivation induces amyloid beta peptide and phosphorylated tau deposits in the brain and cerebrospinal fluid together with altered serotonin metabolism. Thus, it is likely that sleep deprivation is one of the predisposing factors in precipitating Alzheimer's disease (AD) brain pathology. Our previous studies indicate significant brain pathology following sleep deprivation or AD. Keeping these views in consideration in this review, nanodelivery of monoclonal antibodies to amyloid beta peptide (AβP), phosphorylated tau (p-tau), and tumor necrosis factor alpha (TNF-α) in sleep deprivation-induced AD is discussed based on our own investigations. Our results suggest that nanowired delivery of monoclonal antibodies to AβP with p-tau and TNF-α induces superior neuroprotection in AD caused by sleep deprivation, not reported earlier.

Parkinson's disease (PD) in military personnel engaged in combat operations is likely to develop in their later lives. In order to enhance the quality of lives of PD patients, exploration of novel therapy based on new research strategies is highly warranted. The hallmarks of PD include increased alpha synuclein (ASNC) and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) leading to brain pathology. In addition, there are evidences showing increased histaminergic nerve fibers in substantia niagra pars compacta (SNpc), striatum (STr), and caudate putamen (CP) associated with upregulation of histamine H3 receptors and downregulation of H4 receptors in human brain. Previous studies from our group showed that modulation of potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist induces neuroprotection in PD brain pathology. Recent studies show that PD also enhances amyloid beta peptide (AβP) depositions in brain. Keeping these views in consideration in this review, nanowired delivery of monoclonal antibodies to AβP together with ASNC and H3/H4 modulator drugs on PD brain pathology is discussed based on our own observations. Our investigation shows that TiO2 nanowired BF-2649 (1mg/kg, i.p.) or CLBPT (1 mg/kg, i.p.) once daily for 1 week together with nanowired delivery of monoclonal antibodies (mAb) to AβP and ASNC induced superior neuroprotection in PD-induced brain pathology. These observations are the first to show the modulation of histaminergic receptors together with antibodies to AβP and ASNC induces superior neuroprotection in PD. These observations open new avenues for the development of novel drug therapies for clinical strategies in PD.