África Flores

Acute injuries to the central nervous system (CNS) share a rapid disruption of arousal, autonomic stability, and neuroimmune balance. Among the neuromodulatory systems affected, the orexin (hypocretin) network is uniquely positioned at the intersection of wakefulness, autonomic control, and motivated behavior. Experimental evidence across ischemic, hemorrhagic, traumatic, and systemic models shows that orexin signaling is sharply suppressed during the early post-injury collapse and gradually recovers as arousal circuits and homeostatic functions stabilize. Controlled enhancement of orexinergic tone has been found to improve arousal state, modulate inflammatory responses, and support behavioral engagement, although these effects are highly dependent on timing, receptor subtype, and physiological context. This review synthesizes evidence from ischemia, hemorrhagic stroke, traumatic brain and spinal cord injury, and systemic inflammatory states, and examines the conceptual and translational rationale for targeting orexin pathways. We summarize available pharmacological, peptide-based, neuromodulatory, and physiological strategies to boost orexinergic tone, highlighting the growing development of selective OX₂ agonists and experimental approaches to enhance endogenous orexin activity. By integrating findings across etiologies within a timing-aware framework, this review addresses a gap in the current literature, which has largely treated these injuries in isolation. While clinical testing in acute CNS injury has not yet been performed, the mechanistic convergence across etiologies suggests that orexinergic modulation may offer a phase-sensitive means to stabilize arousal and support recovery. Taken together, orexin emerges as a state-dependent integrator whose modulation could complement existing therapies by linking early arousal stabilization with longer-term motivational and functional recovery.

Acute injuries to the central nervous system (CNS) converge on a shared pathophysiology of energetic failure, vascular disruption, and neuroimmune activation. These events destabilize the same metabolic and arousal networks governed by the orexin (hypocretin) system, a hypothalamic hub that synchronizes energy balance, wakefulness, and motivation. Experimental evidence across ischemic, hemorrhagic, traumatic, and systemic models shows that orexin signaling falls sharply during metabolic crisis and gradually reactivates with recovery of vigilance and homeostasis. Controlled enhancement of this system through peptide, pharmacological, or physiological means can limit secondary injury, stabilize autonomic function, and foster motor and cognitive rehabilitation. This review integrates preclinical and clinical evidence linking orexin modulation to neuroprotection and functional restoration, and discusses opportunities and challenges for translating mechanistic insight into therapy. It also outlines practical strategies to enhance orexinergic tone, highlighting the recent development of selective small-molecule orexin agonists and non-invasive delivery routes that make translational exploration increasingly feasible. Orexin emerges as a unifying neuromodulatory target that bridges acute metabolic rescue with long-term behavioral recovery.

Introduction: Chronic pain is a debilitating disease that is usually comorbid to anxiety and depression. Current treatment approaches mainly rely on analgesics but often neglect emotional aspects. Nonpharmacological interventions, such as listening to music, have been incorporated into clinics to provide a more comprehensive management of chronic pain. However, the underlying mechanisms of music-mediated pain relief are not fully understood. Objectives: Our aim was to evaluate the effects and mechanisms of music exposure in an animal model of chronic pain. Methods: We injected mice with the complete Freund adjuvant (CFA) inflammatory agent into the hind paw and housed them for 14 days with background music, or ambient noise, during their active period (Mozart K.205, overnight). The effect of music exposure on nociception, anxiety-like behaviors, and depression-like behaviors was evaluated through different paradigms, including the hot plate, Von Frey, elevated plus maze, splash, and tail suspension tests. In addition, we conducted fiber photometry experiments to investigate whether music influences dopamine dynamics in the nucleus accumbens (NAcc), a crucial region involved in pain processing, anhedonia, and reward. Results: Our findings indicate that music exposure prevents the decrease in NAcc activity observed in CFA-injected mice, linking with a sex-dependent reduction in allodynia, anxiety-like behaviors, and depression-like behaviors. Accordingly, female mice were more sensitive to music exposure than male mice. Conclusion: Collectively, our findings provide compelling evidence for the integration of music as a nonpharmacological intervention in chronic pain conditions. Moreover, the observed effect on NAcc suggests its potential as a therapeutic target for addressing chronic pain and its associated symptoms.

Transcriptomics and phosphoproteomics were carried out in the cerebral cortex of B6.Cg-Mapttm1(EGFP)Klt (tau knockout: tau-KO) and wild-type (WT) 12 month-old mice to learn about the effects of tau ablation. Compared with WT mice, tau-KO mice displayed reduced anxiety-like behavior and lower fear expression induced by aversive conditioning, whereas recognition memory remained unaltered. Cortical transcriptomic analysis revealed 69 downregulated and 105 upregulated genes in tau-KO mice, corresponding to synaptic structures, neuron cytoskeleton and transport, and extracellular matrix components. RT-qPCR validated increased mRNA levels of col6a4, gabrq, gad1, grm5, grip2, map2, rab8a, tubb3, wnt16, and an absence of map1a in tau-KO mice compared with WT mice. A few proteins were assessed with Western blotting to compare mRNA expression with corresponding protein levels. Map1a mRNA and protein levels decreased. However, β-tubulin III and GAD1 protein levels were reduced in tau-KO mice. Cortical phosphoproteomics revealed 121 hypophosphorylated and 98 hyperphosphorylated proteins in tau-KO mice. Deregulated phosphoproteins were categorized into cytoskeletal (n = 45) and membrane proteins, including proteins of the synapses and vesicles, myelin proteins, and proteins linked to membrane transport and ion channels (n = 84), proteins related to DNA and RNA metabolism (n = 36), proteins connected to the ubiquitin-proteasome system (UPS) (n = 7), proteins with kinase or phosphatase activity (n = 21), and 22 other proteins related to variegated pathways such as metabolic pathways, growth factors, or mitochondrial function or structure. The present observations reveal a complex altered brain transcriptome and phosphoproteome in tau-KO mice with only mild behavioral alterations.

Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP (ADCYAP1)-PAC1R (ADCYAP1R1) are highly expressed in the hypothalamus. Here, we show that female mice subjected to acute stress immobilization (IMO) have fear extinction impairments related to Adcyap1 and Adcyap1r1 mRNA upregulation in the hypothalamus, PACAP-c-Fos downregulation in the Medial Amygdala (MeA), and PACAP-FosB/ΔFosB upregulation in the Ventromedial Hypothalamus dorsomedial part (VMHdm). DREADD-mediated inhibition of MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism have impaired fear extinction.

Electrical enabling motor control (eEmc) through transcutaneous spinal cord stimulation offers promise in improving hand function. However, it is still unknown which stimulus intensity or which muscle force level could be better for this improvement. Nine healthy individuals received the following interventions: (i) eEmc intensities at 80%, 90% and 110% of abductor pollicis brevis motor threshold combined with hand training consisting in 100% handgrip strength; (ii) hand training consisting in 100% and 50% of maximal handgrip strength combined with 90% eEmc intensity. The evaluations included box and blocks test (BBT), maximal voluntary contraction (MVC), F wave persistency, F/M ratio, spinal and cortical motor evoked potentials (MEP), recruitment curves of spinal MEP and cortical MEP and short-interval intracortical inhibition. The results showed that: (i) 90% eEmc intensity increased BBT, MVC, F wave persistency, F/M ratio and cortical MEP recruitment curve; 110% eEmc intensity increased BBT, F wave persistency and cortical MEP and recruitment curve of cortical MEP; (ii) 100% handgrip strength training significantly modulated MVC, F wave persistency, F/M wave and cortical MEP recruitment curve in comparison to 50% handgrip strength. In conclusion, eEmc intensity and muscle strength during training both influence the results for neuromodulation at the cervical level.

Electrical enabling motor control (eEmc) through transcutaneous spinal cord stimulation is a non-invasive method that can modify the functional state of the sensory-motor system. We hypothesize that eEmc delivery, together with hand training, improves hand function in healthy subjects more than either intervention alone by inducing plastic changes at spinal and cortical levels. Ten voluntary participants were included in the following three interventions: (i) hand grip training, (ii) eEmc, and (iii) eEmc with hand training. Functional evaluation included the box and blocks test (BBT) and hand grip maximum voluntary contraction (MVC), spinal and cortical motor evoked potential (sMEP and cMEP), and resting motor thresholds (RMT), short interval intracortical inhibition (SICI), and F wave in the abductor pollicis brevis muscle. eEmc combined with hand training retained MVC and increased F wave amplitude and persistency, reduced cortical RMT and facilitated cMEP amplitude. In contrast, eEmc alone only increased F wave amplitude, whereas hand training alone reduced MVC and increased cortical RMT and SICI. In conclusion, eEmc combined with hand grip training enhanced hand motor output and induced plastic changes at spinal and cortical level in healthy subjects when compared to either intervention alone. These data suggest that electrical neuromodulation changes spinal and, perhaps, supraspinal networks to a more malleable state, while a concomitant use-dependent mechanism drives these networks to a higher functional state.

We address some of the current limitations of translational research in fear memory and suggest alternatives that might help to overcome them. Appropriate fear responses are adaptive, but disruption of healthy fear memory circuits can lead to anxiety and fear-based disorders. Stress is one of the main environmental factors that can disrupt memory circuits and constitutes as a key factor in the etiopathology of these psychiatric conditions. Current therapies for anxiety and fear-based disorders have limited success rate, revealing a clear need for an improved understanding of their neurobiological basis. Although animal models are excellent for dissecting fear memory circuits and have driven tremendous advances in the field, translation of these findings into the clinic has been limited so far. Animal models of stress-induced pathological fear combined with powerful cutting-edge techniques would help to improve the translational value of preclinical studies. We also encourage combining animal and human research, including psychiatric patients in order to find new pharmacological targets with real therapeutic potential that will improve the extrapolation of the findings. Finally, we highlight novel neuroimaging approaches that improve our understanding of anxiety and fear-based disorders.

Orexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated. We used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation. Treatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala. These data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867.