The Neuroscientist

Brain-on-a-chip is a microphysiologic platform that comprises cultured brain cells to understand brain disease pathogenesis and treatment. The blood-brain barrier (BBB) of the neurovascular unit serves as a highly selective molecular transport interface for brain homeostasis. BBB dysfunction promotes neuroinflammation, exacerbates disease progression, and contributes to neurodegenerative diseases. However, the mechanisms of BBB disruption underlying brain disorders remain poorly understood; thus, developing neurotherapeutics that can effectively cross the BBB remains a major challenge. Recent advances in microfluidic brain-on-a-chip platforms now enable the creation of BBB-on-a-chip systems that replicate key structural and functional aspects of the human BBB under dynamic flow conditions. Integration of microelectrode arrays into these microfluidic systems enhances their utility by enabling high-throughput drug screening and targeted delivery, allowing real-time monitoring of neuronal activity and network behavior. Although current brain organoid, brain-on-a-chip, and BBB-on-a-chip platforms remain in developmental stages, significant progress has been made using induced pluripotent stem cell–derived neurons, astrocytes, endothelial cells, pericytes, and microglia from healthy individuals and patients with neurodegenerative diseases. This review highlights recent advances in brain- and BBB-on-a-chip technologies and their potential applications in studying disease pathogenesis and preclinical drug screening for neurodegenerative disorders.

Astrocytes play key roles in shaping the synaptic environment, yet the cellular structures through which they interact with individual synapses remain incompletely understood. Perisynaptic astrocytic processes (PAPs) are ultrathin astrocytic leaflets that variably appose synapses and form a major structural interface between astrocytes and neuronal synapses. PAPs are best viewed as a perisynaptic configuration within a broader population of fine astrocytic protrusions, with coverage, geometry, and molecular composition varying across brain regions, developmental stages, and species. In this review, we synthesize current evidence that PAPs define local microdomains around synapses in which astrocytes sense neuronal activity and regulate the synaptic milieu. We discuss how PAP organization and plasticity influence neurotransmitter clearance, ion homeostasis, and structural remodeling at synapses. We also consider how regional differences in PAP organization may contribute to selective circuit vulnerability and how early PAP dysfunction may contribute to synaptic dysfunction in neurodegenerative disease. Finally, we highlight emerging approaches needed to resolve the structure and function of PAP at synapses in vivo and to establish causal mechanisms.

Schizophrenia is a severe mental disorder characterized by a range of symptoms and significant disability, with disrupted proteostasis identified as a critical pathophysiological factor. This comprehensive review evaluates the involvement of heat shock proteins (HSPs) in schizophrenia, highlighting immunologic, genetic, and expression-based evidence, while proposing a potential role for cold shock proteins (CSPs). HSPs, particularly HSP60, HSP70, and HSP90, function as molecular chaperones essential for maintaining proteostasis during stress. HSP autoantibodies are increased in individuals with schizophrenia, and levels correlate with symptom severity, blood–brain barrier dysfunction, and response to antipsychotics such as clozapine. Genetic research links HSP gene polymorphisms (e.g., HSPA1A, HSPA1B, and HSPB1) to disease risk, symptom severity, and treatment outcomes. Altered HSP levels in brain regions like the dorsolateral prefrontal cortex suggest roles in neuroprotection, oxidative stress, and synaptic dysfunction. Antipsychotics modulate HSP expression, indicating potential for precision medicine using HSP coinducers like BGP-15. While HSPs are well linked to schizophrenia, limited evidence suggests that CSPs could affect deficits in synaptic structure and pruning, known to play a role in schizophrenia, through actions involving BDNF-TrkB signaling. Despite recent advancements, challenges remain in achieving consistent immune responses, ensuring genetic relevance across populations, and fully understanding the importance of CSPs, which calls for longitudinal multiomics studies, diverse cohort analyses, and advanced preclinical models. This review positions HSPs as central to the molecular framework of schizophrenia and CSPs as a largely unexplored area, advocating for integrated research to enhance mechanistic understanding and therapeutic approaches for this complex disorder.

The left ventral premotor cortex (PMv) has not been fully acknowledged as a key component of the brain’s network for reading. This region, corresponding to Brodmann area (BA) 6, is cytoarchitecturally distinct from adjacent Broca’s area (BA44/45) and primary motor cortex (BA4) and specifically involved in articulatory codes for speech production. The left PMv is known to receive direct white matter projections from posterior brain regions responsible for visual and phonological processing. Consequently, the region plays a significant role in reading when the expert visual word-form system in the left occipitotemporal cortex is underdeveloped or compromised in early literacy development in childhood or in neurologic disorders in adulthood. Recent functional neuroimaging and brain stimulation studies further suggest that those direct neural pathways connecting the left PMv with the occipital cortex are fully functioning in literate adults, rapidly generating speech motor codes at a very early stage of reading, and faster than thought previously. This region may therefore serve as an alternative and promising cortical target for future neuromodulation research aimed at boosting cognitive components involved in reading.

Endurance exercise can induce a transient euphoric state known as the runner’s high, characterized by euphoria, anxiolysis, hypoalgesia, and a subjective sense of flow. Traditionally, this phenomenon has been interpreted within an “either–or” framework, attributing its emergence primarily to β-endorphins or, more recently, to the endocannabinoid (eCB) system. The aim of this narrative review is to move beyond this dichotomy and to present an integrative neuromodulatory perspective on the runner’s high, with a focus on the eCB system as a central coordinating mechanism. We integrate evidence from human and animal studies showing that circulating eCBs reliably increase during moderate-intensity endurance exercise and are consistently associated with core affective features of the runner’s high. At the same time, we consider the complementary roles of other neuromodulators: β-endorphins primarily regulate pain and stress responses; brain-derived neurotrophic factor supports neuroplasticity; serotonin and dopamine modulate mood and motivation; noradrenaline and adrenaline facilitate arousal; and leptin links the metabolic state to movement and motivation. Overall, the runner’s high appears to reflect an orchestrated neuromodulatory response in which the eCB system occupies a prominent integrative role.