Alterations in Blood-Brain Barrier Integrity and Lateral Ventricle Differ in Rats Exposed to Space Radiation and Social Isolation.

The proposed Mars missions will expose astronauts to long durations of social isolation (SI) and space radiation (SR). These stressors have been shown to alter the brain's macrostructure and microenvironment, including the blood-brain barrier (BBB). Breakdown of the BBB is linked to impaired executive functions and physical deficits, including sensorimotor and neurocognitive impairments. However, the precise mechanisms mediating these effects remain unknown. Additionally, the synergistic effects of combined exposure to SI and SR on the structural integrity of the BBB and brain remain unknown. We assessed the BBB integrity and morphology in the brains of male rats exposed to ground-based analogs of SI and SR. The rats exposed to SR had enlarged lateral ventricles and increased BBB damage associated with a loss of astrocytes and an increased number of leaky vessels. Many deficits observed in SR-treated animals were attenuated by dual exposure to SI (DFS). SI alone did not show BBB damage but did show differences in astrocyte morphology compared to the Controls. Thus, determining how single and combined inflight stressors modulate CNS structural integrity is crucial to fully understand the multiple pathways that could impact astronaut performance and health, including the alterations to the CNS structures and cell viability observed in this study.

Evidence for a role of the basolateral amygdala in regulating regional metabolism in the stressed brain.

The brain regulates every physiological process in the body, including metabolism. Studies investigating brain metabolism have shown that stress can alter major metabolic processes, and that these processes can vary between regions. However, no study has investigated how metabolic pathways may be altered by stressor perception, or whether stress-responsive brain regions can also regulate metabolism. The basolateral amygdala (BLA), a region important for stress and fear, has reciprocal connections to regions responsible for metabolic regulation. In this study, we investigated how BLA influences regional metabolic profiles within the hippocampus (HPC) and medial prefrontal cortex (mPFC), regions involved in regulating the stress response and stress perception, using optogenetics in male C57BL/6 mice during footshock presentation in a yoked shuttlebox paradigm based on controllable (ES) and uncontrollable (IS) stress. RNA extracted from HPC and mPFC were loaded into NanoString® Mouse Neuroinflammation Panels, which also provides a broad view of metabolic processes, for compilation of gene expression profiles. Results showed differential regulation of carbohydrate and lipid metabolism, and insulin signaling gene expression pathways in HPC and mPFC following ES and IS, and that these differences were altered in response to optogenetic excitation or inhibition of the BLA. These findings demonstrate for the first time that individual brain regions can utilize metabolites in a way that are unique to their needs and function in response to a stressor, and that vary based on stressor controllability and influence by BLA.

Localization and neurochemical identity of alpha1-adrenergic receptor-containing elements in the mouse locus coeruleus.

The locus coeruleus (LC) is the major source for norepinephrine (NE) in the brain and projects to areas involved in learning and memory, reward, arousal, attention, and autonomic functions related to stress. There are three types of adrenergic receptors that respond to NE: alpha1-, alpha2-, and beta-adrenergic receptors. Previous behavioral studies have shown the alpha1-adrenergic receptor (α1AR) to be present in the LC, however, with conflicting results. For example, it was shown that α1ARs in the LC are involved in some of the motivational effects of stimulation of the medial forebrain bundle, which was reduced by α1AR antagonist terazosin. Another study showed that during novelty-induced behavioral activation, the α1AR antagonist prazosin reduced c-fos expression in brain regions known to contain motoric α1ARs, except for the LC, where c-fos expression was enhanced. Despite new research delineating more specific connectivity of the neurons in the LC, and some roles of the adrenergic receptors, the α1ARs have not been localized at the subcellular level. Therefore, in order to gain a greater understanding of the aforementioned studies, we used immunohistochemistry at the electron microscopic (EM) level to determine which neuronal or glial elements in the LC express the α1AR. We hypothesized, based on previous work in the ventral periaqueductal gray area, that the α1AR would be found mainly presynaptically in axon terminals, and possibly in glial elements. Single labeling immunohistochemistry at the EM revealed that about 40% of labeled elements that contained the α1AR were glial elements, while approximately 50% of the labeled neuronal elements were axon terminals or small unmyelinated axons in the LC. Double labeling immunohistochemistry found the α1AR expressed in GFAP-labeled astrocytes, in both GABAergic and glutamatergic axon terminals, and in a portion of the α1AR dendrites, colocalized with tyrosine hydroxylase (TH, a marker for noradrenergic neurons). This study sheds light on the neuroanatomical framework underlying the effects of NE and pharmaceuticals acting directly or indirectly on α1ARs in the LC.

Targeted NMDA Receptor Interventions for Autism: Developmentally Determined Expression of GluN2B and GluN2A-Containing Receptors and Balanced Allosteric Modulatory Approaches.

Various ASD risk alleles have been associated with impairment of NMDA receptor activation (i.e., NMDA Receptor Hypofunction) and/or disturbance of the careful balance between activation mediated by GluN2B-subtype and GluN2A-subtype-containing NMDA receptors. Importantly, although these various risk alleles affect NMDA receptor activation through different mechanisms, they share the pathogenic consequences of causing disturbance of highly regulated NMDA receptor activation. Disturbances of NMDA receptor activation due to sequence variants, protein termination variants and copy number variants are often cell-specific and regionally selective. Thus, translational therapeutic NMDA receptor agonist interventions, which may require chronic administration, must have specificity, selectivity and facilitate NMDA receptor activation in a manner that is physiologic (i.e., mimicking that of endogenously released glutamate and glycine/D-serine released in response to salient and relevant socio-cognitive provocations within discrete neural circuits). Importantly, knockout mice with absent expression and mice with haploinsufficient expression of the deleterious genes often serve as good models to test the potential efficacy of promising pharmacotherapeutic strategies. The Review considers diverse examples of "illness" genes, their pathogenic effects on NMDA receptor activation and, when available, results of studies of impaired sociability in mouse models, including "proof of principle/proof of concept" experiments exploring NMDA receptor agonist interventions and the development of promising positive allosteric modulators (PAMs), which serve as support and models for developing an inventory of PAMs and negative allosteric modulators (NAMs) for translational therapeutic intervention. Conceivably, selective PAMs and NAMs either alone or in combination will be administered to patients guided by their genotype in order to potentiate and/or restore disrupted balance between activation mediated by GluN2B-subtype and GluN2A-subtype containing NMDA receptors.