The neuronal endoplasmic reticulum (ER) forms a continuous membrane network that extends throughout the soma, dendrites, axons, and synaptic compartments. Although traditionally viewed as a structurally continuous intracellular organelle, recent advances in volume electron microscopy, super-resolution imaging, and live-cell functional analyses have revealed that the ER is highly compartmentalized into specialized structural and molecular domains. These domains organize local Ca[2+] release, store refilling, luminal Ca[2+] redistribution, and inter-organelle communication through membrane contact sites, thereby enabling the diverse physiological functions of the ER. Emerging evidence further indicates that ER topology is a fundamental determinant of diverse ER functions and that disruption of ER architecture is increasingly implicated in the pathogenesis of neurological disorders. In this review, I first summarize the ultrastructural organization of the neuronal ER based on representative electron microscopy observations and then discuss how spatial compartmentalization provides an organizational principle linking ER structure to intracellular signaling, neuronal homeostasis, and neurological disorders.

The hippocampus, a brain region intimately associated with memory, has been the subject of intense research interest for more than half a century. These efforts have produced a number of theories that postulate links between hippocampal components and specific aspects of memory processing. However, progress in the field has been hindered by a surprising lack of information about the propagation of signals from the cortex across the full-length hippocampal circuit. Recent experimental work addressed this problem and found that activation of an input from the cortex elicits an entirely unexpected response by the CA1 output station. Subsequent work identified the pathways and local operations responsible for the pertinent signal transformations. Stimulation of the input with behaviorally relevant frequencies uncovered filtering, amplification, and cycling operations executed by the various links and nodes of the circuit. Collectively, the results indicate that the system switches among different operating modes-as such, we propose that these modes are associated with distinctly different spiking patterns by CA3 pyramidal cells. In any case, circuit analysis suggests that the hippocampus makes multiple, diverse contributions to physiology and behavior via dynamic states initiated by ever-changing patterns of input from the cortex and lower brain.

The brainstem theory of consciousness asserts that raw, subjective experience, the "me inside," derives from computations implemented in the brainstem, not the cortex. The argument rests on philosophy's prototypical example of sentience, pain. Feeling pain does not require cortical processing. Nowhere in the cortex does electrical stimulation reliably evoke pain. Subcortical stimulation does. Painful epileptic seizures are rare. Cortical lesions do not eliminate pain or cause loss of consciousness (LOC). Indeed, some individuals with near-complete cortical loss are sentient. Focal brainstem lesions, however, often cause LOC/coma, as do anesthetics delivered to these same foci (general anesthesia). Clearly, peripheral nociceptor input can be translated into conscious pain experience by the "primitive" brainstem. Fish and reptiles respond to threats using vision, sound, and olfaction, but this capacity is rudimentary. Except for pain, advanced sensory feature extraction requires the supercomputer-like capacity of the mammalian cerebral cortex, available evolutionarily only eons after reptiles. Rather than reinventing sentience circuitry with cortical architecture, evolution exploited the sentience-of-pain capability long functioning in the brainstem with the aid of dedicated axonal pathways. This explains why large cortical lesions disrupt "consciousness of" specific things, without causing unconsciousness, while focal brainstem lesions erase all sentience, including pain, sending the individual into oblivion.

Why is NMNAT2 (and the NAD-NMNAT2-SARM1 axis) important? Axon loss is a common and early driver of disability across neurodegenerative diseases, peripheral neuropathies, traumatic injury, and neurotoxic chemotherapy. A major conceptual advance from the Wallerian degeneration research field is that axons can execute an intrinsic self-destruction program (programmed axon degeneration) that is actively suppressed in healthy axons. NMNAT2 acts as the central endogenous axon maintenance factor in this system: it is highly labile; it must be continuously delivered from the soma into axons; and when its levels fall, axon degeneration is triggered through activation of SARM1, an NAD-consuming enzyme. This makes NMNAT2 a mechanistically grounded therapeutic node: stabilizing it, improving axonal delivery, or blocking downstream SARM1 can strongly preserve axons in diverse injury and disease contexts. NMNAT2 is a short-lived axonal NAD biosynthetic enzyme that maintains a low NMN:NAD ratio to restrain the executioner SARM1, thereby preserving axon integrity. This review integrates NMNAT2's localization-dependent pools, turnover mechanisms, upstream stressors, downstream SARM1 signaling, and engineered and disease-associated variants. A localization-aware representation of NMNAT2's functions, trafficking, proteostatic regulation, upstream stressors, and genetic variants should enable targeted experimental design and therapeutic hypothesis generation aimed at stabilizing axons. Here the functional landscape and localization of NMNAT2 in neurodegeneration is examined, ending with gaps identified in the literature and strategies to address these.

The vagus nerve constitutes a core bidirectional pathway linking the central nervous system with peripheral organs and plays a fundamental role in gut-brain communication. Beyond its classical autonomic functions, accumulating evidence positions vagal signaling as a candidate integrative mechanism through which visceral, immune, and microbial inputs may modulate stress regulation, affective processing, cognition, and neuroplasticity. This narrative review synthesizes current anatomical and physiological knowledge of vagal pathways, with emphasis on afferent projections to the nucleus tractus solitarius and downstream modulation of noradrenergic, serotonergic, and cholinergic circuits involving the locus coeruleus, hippocampus, and prefrontal cortex. We further examine vagus nerve stimulation, including invasive and noninvasive approaches, as a neuromodulatory strategy for neurological and psychiatric disorders. Evidence is reviewed for its effects in epilepsy, mood and anxiety disorders, cognitive impairment, and neurodegenerative conditions, highlighting mechanisms such as synaptic plasticity enhancement, neuroimmune modulation, and regulation of hypothalamic-pituitary-adrenal axis activity. While findings support the translational relevance of vagal modulation, variability in stimulation parameters and outcome measures limits cross-study comparison. Greater methodological standardization and integration of neurocognitive endpoints are required to clarify its clinical and neuroscientific significance.

Although spina bifida (SB) and tethered cord syndrome (TCS) are often discussed and studied as separate conditions, their co-occurrence is common, clinically consequential, and understudied, particularly with respect to neurogenic bladder and bowel dysfunction. SB arises from incomplete neural tube closure, whereas TCS involves abnormal fixation of the spinal cord, often leading to progressive neurologic deficits. SB affects approximately 3.63 per 10,000 live births in the United States, and TCS occurs in a significant proportion of affected individuals; however, the true incidence of their co-occurrence remains unknown. Current clinical strategies include surgical intervention and symptomatic management, but long-term outcomes are variable, and gaps persist in diagnosis, presentation, and optimal treatment. Bladder and bowel dysfunction are among the most prevalent and functionally impactful complications, yet these outcomes are inconsistently documented and rarely tracked longitudinally. Preclinical models in rodent, porcine, ovine, and feline species provide insight into spinal cord development, tethering mechanisms, and functional consequences, but few examine bladder or bowel function. This review synthesizes clinical and preclinical evidence to characterize overlapping SB and TCS presentations, identifies gaps in bladder and bowel outcome reporting, and highlights opportunities to improve translational animal models and long-term care.

This review examines how distributed neural circuits involving the hippocampus, entorhinal cortex, and neocortex collectively support learning and memory functions. The hippocampus and entorhinal cortex are densely and bidirectionally connected, forming a core circuit that supports the formation of episodic memories as well as spatial learning and navigation. Their interactions with neocortical regions underlie decision making and the transformation of episodic experience into abstract concepts. These functions are supported by precisely timed interactions between neuronal ensembles across distributed circuits, coordinated by neural oscillations. During learning and navigation, theta oscillations synchronize the firing of neuronal ensembles and mediate the flow of information across structures. During periods of rest and sleep, hippocampal sharp-wave ripples coordinate the reactivation of experience-related activity patterns. Sharp-wave ripples mediate the transfer of memory traces from the hippocampus to the neocortex and their long-term consolidation. Rather than a unidirectional transfer from hippocampus to neocortex, emerging evidence reveals continuous bidirectional interactions throughout memory encoding, consolidation, and retrieval. Critically, recurrent processing loops among the entorhinal cortex, hippocampus, and neocortex enable ongoing updating and integration of memory representations, challenging traditional sequential processing models and emphasizing the dynamic and interactive nature of these circuits.

This article examines the claim that Michelangelo's The Creation of Adam contains an anatomical depiction of the human brain. By integrating semiotic theory and neuropsychology, it explores how meaning in visual art emerges through the interaction between artistic form and perceptual processes. While semiotics emphasizes that symbols gain meaning through interpretation rather than fixed reference, neuropsychology shows that perception is constructive, shaped by predictive processing, pattern recognition, and phenomena such as pareidolia. The analysis suggests that the hidden brain may reflect either intentional symbolic design or the observer's cognitive tendency to impose structure on ambiguous imagery. Ultimately, the study argues that meaning arises relationally between artwork and viewer rather than residing exclusively in either.