The capacity for excess manganese to alter dopaminergic systems resulting in neurobehavioral deficits is clear, yet far less is known the impact of chronic, lower, sub-toxic manganese exposures. Manganese exposure may affect dopamine synthesis and metabolism, and as such impact drug efficacy. These may also occur to a greater extent in populations with genetic variants that render them more vulnerable to intellectual developmental disabilities. DATT356M/+ mice were used as a model of altered dopamine transport via an autism-linked single nuclear polymorphism in the dopamine transporter. Following 12 weeks feeding of manganese (2400 ppm) mild changes in spontaneous and repetitive behaviors such as climbing and rearing were induced by both genotype and manganese although the patterns differed according to age and sex. Female mice also exhibited a decrease in activity in response to amphetamine compared to control-fed mice (70 ppm) littermates independent of the decreased response observed in DATT356M/+ mice. Males showed a more robust effect of genotype suppression of the amphetamine response but no further effect of manganese. Behavioral changes occurred in the absence of significant impact of dietary manganese on body weight. Manganese exposure was associated with altered gene expression in nucleus accumbens relating to metal transport (Slc11a2, Slc39a8, Slc39a14, Slc30a10) and dopamine regulation (TH, Slc6a3) that did not show clear differences according to sex. Changes at the RNA level were not replicated in protein expression changes measured in the striatum. There were no changes in levels of dopamine or metabolites in the cortex according to genotype or manganese, although manganese exposure was associated with decreased norepinephrine and increased serotonin. SNCA has a regulatory role in dopamine neurotransmission and snca gene expression was significantly down regulated by both DATT356M/+ genotype and manganese diets. The altered dopamine changes and response to amphetamine between sexes in presence of Mn highlights the potential role of sub-toxic exposures to heavy metals in moderating behavioral profiles and drug responses. The lack of consistent differences according to sex, genotype and exposure across all outcomes also suggests the complexity of the specific pathways and mechanisms driving the behavioral differences.

Septic shock, a severe, life-threatening infection resulting in organ failure, has seen no successful, novel therapies emerge in the past two decades. In addition to hypoperfusion and inflammation, organ dysfunction in septic shock is caused by microvascular, mitochondrial, and immune dysfunction. Animal studies support the use of hyperbaric oxygen treatment to improve mitochondrial function and reduce the inflammatory cascade, suggesting a potential role for hyperbaric oxygen in treating septic shock.

Arteriolar regulation is central to maintaining adequate tissue perfusion, and its disruption can lead to adverse health outcomes. However, mechanisms governing vessel responses to complex environmental conditions within a network context remain uncertain. This study presents computational simulations of arteriolar network responses to various combinations and intensities of five physiologically significant stimuli: metabolic (via adenosine), adrenergic (via norepinephrine), oxygen, myogenic (intralumenal pressure), and blood flow/shear stress. Individual vessel diameter adaptations are predicted using machine learning models trained on extensive experimental data of arteriolar responses to stimuli combinations in rat skeletal muscle. After evaluating multiple single vessel modeling pipelines, a high-performing machine learning vessel model (R[2] > 0.9) was applied to an initially static (i.e., non-regulating) network to obtain a novel steady-state network regulation model. The initial static arteriolar network was obtained via a previously described experimentally validated constrained constructive optimization (CCO) approach. Regulated network characteristics are analyzed based on diameter distribution and over a range of hemodynamic properties (volumetric blood flow, red blood cell flow, tube and discharge hematocrit) relevant to tissue health. These simulations support a range of research objectives, allowing user adjustments to network properties (e.g., vessel density), tissue shape/size, and environmental conditions (i.e., varying intensities and combinations of the five vasoactive stimuli). The methodology in this study promotes accessible modeling and holds application in disease research or therapy developments, as well as permitting further theoretical development such as time-dependent network regulation.

The locus coeruleus-noradrenergic (LC-NE) system is a central neuromodulatory network involved in regulation of arousal, attention, and adaptive behavioral function. Chronic stress has been associated with altered LC activity, including shifts in tonic-phasic regulation, yet the direction, magnitude, and persistence of these alterations appear to depend on stress paradigm, duration, and context, and the biological mechanisms underlying the emergence and persistence of this dysregulated state remain incompletely understood. Here, we examine how prolonged stress exposure may contribute to LC-NE dysfunction through interacting cellular and axonal mechanisms. Prolonged corticotropin-releasing factor (CRF)-mediated activation is proposed to impose a chronic tonic load on LC neurons, increasing metabolic demand, calcium burden, and mitochondrial oxidative stress. Because LC neurons combine autonomous pacemaking activity with exceptionally extensive axonal arborization, prolonged stress exposure is likely to promote cumulative cellular strain, impaired intracellular transport, and reduced efficiency of distal norepinephrine signaling. Within this model, chronic stress is conceptualized as producing a loss of dynamic regulatory capacity-a reduced ability of the LC-NE system to shift flexibly between tonic and phasic modes of signaling-rather than simply a quantitative increase or decrease in norepinephrine levels, even in the absence of overt neuronal loss. Disruption of tonic-phasic signaling balance, reduced phasic responsiveness, impaired autoregulatory function, and diminished neuromodulatory flexibility could collectively contribute to persistent alterations in network regulation and cognitive function. This perspective reframes stress-related dysfunction as a progressive, cumulative process rather than a transient alteration in stress signaling alone. By linking chronic stress exposure to LC-NE dysfunction through integrated cellular and axonal mechanisms, this work provides a mechanistic basis for understanding persistent stress-related alterations in brain function and highlights restoration of adaptive LC-NE regulation as a potential therapeutic principle. The proposed framework integrates systems-level stress physiology with cellular and axonal neurobiology into a unified model of stress-induced LC-NE dysfunction.

This review examines age-related hair greying as a potential imbalance in the HFSC-MeSC-niche network in terms of time, space and signal quality. We define signal quality as the effective strength, temporal precision and noise-to-threshold relationship of niche-derived cues that regulate MeSC activation. We propose that ageing may progressively weaken the temporal coordination between HFSC activation and MeSC responsiveness. ECM remodelling and altered guidance-related cues may further impair MeSC niche engagement. Meanwhile, chronic oxidative stress, low-grade inflammation and stress-related sympathetic norepinephrine signalling may increase background noise, distort signal timing and push the MeSC activation threshold upward, so residual MeSC-lineage cells may fail to engage effectively with the niche. Such functional uncoupling may represent an early or intermediate stage, whereas sustained genotoxic stress or niche failure can eventually drive irreversible MeSC depletion. Based on this, the article constructs an integrative model, emphasizing that future intervention strategies may need to shift from simply protecting MeSCs to preserving the temporal and spatial coupling of the HFSC-MeSC-niche network. Potential approaches may include reducing chronic niche stress, maintaining HFSC-MeSC communication, preserving ECM organization and improving the timing and strength of pro-pigmentation cues. We further propose that hair greying may provide an accessible visual readout of stem-cell niche ageing.

Vascular function depends on arterial stiffness and volume dynamics; however, segmental differences remain unclear. Segmental arterial stiffness can be assessed using a cardio-ankle vascular index (CAVI)-based stiffness parameter (segmental-β), and volume changes can be estimated using intravascular ultrasound (IVUS). In this study, segmental-β and arterial caliber changes in the aorta and iliofemoral arteries were investigated during noradrenaline (NAD) administration with the aim of clarifying segmental vascular function and its interactions. Anesthetized rabbits received low, medium, and high NAD doses (10, 100, and 1000 μg/kg) and hemodynamic parameters were measured. The results showed that blood pressure and peripheral vascular resistance increased in a dose-dependent manner. IVUS demonstrated dose-dependent increases in arterial caliber in both the aorta and iliac arteries, as well as in estimated aortic volume. At low and medium NAD doses, iliac-β increased, whereas aortic-β decreased. In contrast, at the high NAD dose, iliac-β turned downward, and aortic-β turned upward. Despite uniform arterial dilation associated with volume centralization induced by peripheral arteriolar vasoconstriction, arterial stiffness exhibited reciprocal segmental changes. Overall, this intersegmental vascular response may be conceptualized as an "arterial ballooning chain effect" involving elastic arteries, muscular arteries, and arterioles under strong vasoconstrictive stress. This phenomenon might be an adaptation of central blood pooling among various arterial trees.

Autoimmune diseases arise from a breakdown of immune tolerance, yet the mechanisms that initiate tissue-specific autoimmunity remain poorly understood[1-4]. Here we identify a two-hit mechanism in which immune dysregulation and physiological neural activation converge to trigger autoimmune alopecia. We show that transient depletion of regulatory T (Treg) cells during the anagen phase of the hair cycle, but not during telogen, induces CD8[+] T-cell-mediated destruction of immune-privileged hair follicle stem cells (HFSCs), resulting in hair loss. This anagen-restricted susceptibility depends on sympathetic nerve activity, which is physiologically elevated during anagen: sympathetic denervation prevents disease, whereas psychological stress or optogenetic activation of sympathetic nerves renders otherwise resistant telogen skin susceptible to autoimmune attack after Treg cell depletion. Mechanistically, sympathetic noradrenaline signalling through HFSC-intrinsic ADRB2 promotes physiological reactivation of endogenous retroviruses (ERVs) in anagen HFSCs. Under conditions of Treg cell depletion, this ERV-associated state drives autoimmune pathology by engaging AIM2-dependent innate immune activation and pathogenic CD8[+] T cell responses. Accordingly, genetic ablation of Aim2 or pharmacological inhibition of ERV reverse transcription protects against disease development. Together, these findings show that physiological sympathetic activity establishes a transiently vulnerable epithelial state, whereas Treg cells prevent this state from progressing to tissue-specific autoimmunity. This neuro-epithelial-immune circuit links hair-cycle state to the breach of HFSC immune privilege and the initiation of autoimmune alopecia.

We here report the discovery of a series of fluoro-substituted 3-phenoxy-azetidines useful for modulating levels of monoamines in cerebral cortical areas of the brain. The compounds were characterized by in vivo studies using, in particular, behavioural, and microdialysis methods. Furthermore, the compounds were tested in binding assays for the human serotonin (5-HT), noradrenaline (NA), and dopamine (DA) transporters in order to assess the risk for addiction/dependency. Optimization of this class of compounds for improving cognitive functions while minimizing the effect on monoamine transporters resulted in the selection of a candidate drug 1 (IRL757). After 1 was successfully assessed in different animal models for motivation/goal-directed behaviour (unpublished data), it is currently being evaluated in humans for the treatment of apathy in neurological disorders in general, and in particular in Parkinson's disease (PD).

Rats emit 50-kHz ultrasonic vocalizations (USVs), a widely used measure of drug-induced motivational and affective effects and dopaminergic activity. Although psychedelic drugs are promising for addiction treatment, the effects of ayahuasca (AYA) on 50-kHz ultrasonic vocalizations (USVs) remain unclear. We investigated whether acute AYA treatment attenuates lisdexamfetamine (LDX)-induced USVs, hyperlocomotion and monoaminergic content in adult male Wistar rats. Rats were pretreated with vehicle (VEH) or LDX (10 mg/kg). Forty minutes later, they received VEH or AYA (240 mg/kg) treatment. Behavioral testing was conducted 20 min later in a previous habituated arena during 20 min. Nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were dissected for monoaminergic content analysis by HPLC. AYA treatment reduced the numbers of total 50-kHz, trill and flat USV in VEH and LDX-pretreated groups, with a greater effect size in trill calls. Additionally, AYA attenuated spontaneous locomotion without affecting the LDX-induced hyperlocomotion. The pretreatment with LDX or that with AYA increased the dopamine content in the NAc, but only AYA treatment reduced DOPAC content. All treatments reduced dopamine turnover, as indicated by the DOPAC/dopamine ratio. In the mPFC, AYA treatment increased noradrenaline and decreased serotonin levels without changing their turnover. Both AYA and LDX increased dopamine turnover without altering dopamine content, and AYA did not alter the effects of LDX. Together, these findings suggest that AYA attenuates LDX-induced positive affective responses without reducing hyperlocomotion, accompanied by changes in noradrenaline and serotonin levels in the mPFC and dopamine levels in the NAc.

Melatonin (MEL) is an endogenous hormone that regulates circadian rhythm, immune function and oxidative stress responses. Norepinephrine (NE), an endogenous catecholamine, increases blood pressure through the sympathetic nervous system and is commonly administered intraoperatively or in the clinically ill patient for hemodynamic support. Although endogenous NE is known to stimulate MEL synthesis, the effects of exogenous intravenous NE on plasma MEL concentration, particularly under general anaesthesia (GA), remain poorly characterised. This study examined the influence of intravenous NE on plasma MEL concentrations in healthy volunteers, both awake and under general anaesthesia. A secondary analysis was conducted using data from a prospective, single-centre, cross-over study involving volunteers who received stepwise NE infusions while awake and under total intravenous general anaesthesia. Arterial blood samples were collected to determine plasma MEL and NE concentrations. Linear mixed-effects modelling was used to assess the relationship between NE and MEL concentrations. A total of 36 healthy volunteers were enroled, yielding 417 MEL-NE samples. Intravenous NE administration was significantly associated with higher plasma MEL concentration, corresponding to an estimated 26% increase in MEL per 1 standard-deviation increase in NE concentration (Estimate = 0.230, p < 0.001). MEL concentrations were approximately 43% higher in the awake phase compared to GA (Estimate = 0.356, p < 0.001). GA did not significantly modify the NE-MEL association (Estimate = -0.02877, p = 0.528). Substantial positive correlation was observed between baseline MEL concentrations and the magnitude of the response to NE administration (r = 0.74). In conclusion, intravenous NE increases plasma MEL concentrations in both awake and anaesthetised individuals. Substantial interindividual variation in MEL response suggests underlying physiological differences. Future studies should explore the long-term effects of NE administration on MEL concentrations. Trial Registration: The study is registered in the Dutch Trial Register (NL9312).