Arianna Maffei

The fascination with the brain as the seat of sensation and thought is long-standing.Descriptions of the effects of sedatives such as alcohol and opium and of the consequences of head injury date back to ancient Egypt (Krikorian, 1975;Sanchez and Burridge, 2007), and accounts of epilepsy to ancient Greece (Karamanou et al., 2017;Tsoucalas et al., 2017).Over the millennia many ideas about the anatomy and function of the brain were proposed, but the pivotal step towards our current understanding was the discovery of bioelectricity by Luigi Galvani in the late 1700s. Galvani's demonstration that animal tissue can generate electricity, and the debate it sparked with the physicist Alessandro Volta, drove the technological and conceptual advances that gave rise to cellular neurophysiology as we know it today (Piccolino, 1998;Verkhratsky and Parpura, 2014). Continued innovation and careful experimentation then established the properties of excitable membranes, the cellular organization of the brain, and the mechanisms of electrochemical signalling. This interplay between discovery and technology development continues, as every finding opens challenging new questions about brain function in health and disease. In this brief opinion we highlight the avenues of research in cellular neurophysiology that we, as editors, find particularly compelling.Advances in anatomical, electrophysiological and molecular approaches have greatly expanded our ability to identify the diverse cell populations of brain tissue. Brain cells can be classified by morphology, location, electrophysiological properties, neurotransmitter identity, expression of specific proteins and full transcriptomic analysis (DeFelipe et al., 2013;Network, 2021;Chi et al., 2023;Gao et al., 2025;Jongbloets et al., 2026). In all species, from insects to humans, brain tissue comprises two major cell groups, neurons and glia. Neurons are broadly classified as excitatory or inhibitory according to the effect they exert on their postsynaptic targets, and are further distinguished by the transmitters they release and by other molecular markers they express. Glial cells show comparable diversity in morphology, molecular signature and function.Important debates about what actually defines a cell type remain unresolved (Zeng, 2022).Detailed molecular profiling has dramatically increased the number of candidate cell types, sometimes yielding classifications that are inconsistent across research groups or analytical pipelines (Network, 2021;Yao et al., 2023). This increase in molecular resolution is powerful when paired with other criteria, as multimodal approaches such as Patch-seq illustrate by acquiring electrophysiology, morphology and transcriptome from the same neuron (Cadwell et al., 2016;Gouwens et al., 2020;Lee et al., 2023). Even so, the field still needs agreed strategies for mapping molecular, morphological and functional parameters onto one another, and a clearer criterion for what combination of parameters defines an actual cell type as opposed to a transient cellular state (Zeng, 2022;Gao et al., 2025). Mapping cell types across species is a related and equally open problem: broad categories such as glutamatergic and GABAergic neurons are well conserved, yet finer morphological and molecular divisions are hard to reconcile (Hodge et al., 2019;Berg et al., 2021). Spatial transcriptomics paired with functional recordings is a promising route towards resolving these questions.A second line of open inquiry concerns how cell types interact. Are there connectivity modules that repeat across brain regions, or across areas, with comparable function in different species? Or are modules region-specific, shaped by the functional demands of a particular circuit? The possibility of canonical structures such as cortical columns or microcircuits is appealing, because it would reduce the complexity of neural networks to a manageable set of functional units. Evidence for such structures exists in several species (Mountcastle, 1997;Adams and Horton, 2009), but their functional implications remain debated (Martin and da Costa, 2010). Molecular approaches now allow neurons derived from a common precursor to be tracked (Brown et al., 2011;Li et al., 2012;Lin et al., 2023), testing whether shared origin biases connectivity and thereby contributes to module formation. In parallel, large-scale anatomical reconstruction (connectomics) is being used to chart circuit organization (Abbott et al., 2020;Celii et al., 2025;Ding et al., 2025;Dorkenwald et al., 2025;Gamlin et al., 2025;Weis et al., 2025). These approaches are technically demanding and depend on the development of new analytical tools and access to substantial computational power. As both advance, the identification of connectivity motifs within and across brain regions becomes a realistic goal, provided that structural motifs are validated against physiological measurements of what those connections actually do.A fundamental aspect of neurophysiology is the study of excitable membranes and how their properties shape communication between brain cells. Great advances have been made in understanding neuronal excitability, synaptic transmission, electrical coupling and neuron-glia interactions. Genomic analyses have greatly expanded our view of the diversity of voltage-gated ion channels across species and cell types (Davila-Velderrain and Giese, 2025), while electrophysiological work has quantified the properties of distinct channels and receptor families and of individual members within them (Ranjan et al., 2011;Tripathy et al., 2017). This diversity underlies the characteristic excitability of neuronal and glial cell types. The subcellular location and clustering of specific channels can further confer specialized properties on particular compartments, such as the axon initial segment (Kerti et al., 2012;Nusser, 2012), or amplify synaptic inputs in distal dendrites (Park et al., 2025). Gap junctions...

Cortical neurons in sensory areas undergo a protracted process of postnatal maturation that includes changes in membrane properties, synaptic drive and connectivity. The completion of this process is associated with the closure of critical periods for experience-dependent plasticity in visual, auditory and somatosensory cortices. Whether these findings extend to the postnatal development of cortical circuits for taste is currently unknown. Taste receptor cells in the taste buds reliably fire action potentials in response to taste stimuli by the third postnatal week and show extended refinement of membrane excitability into adulthood. Taste responsive neurons in the nucleus of the solitary tract show reorganization of peripheral nerve terminals (NTS) over a timeline comparable to taste buds. However, no study to date investigated the postnatal development of neurons in the gustatory cortex (GC). Here, we focused on pyramidal neurons in the deep layers of GC in acute slices from male and female mice and compared their membrane properties from the third to the eighth postnatal week. We report changes in intrinsic excitability and a shift of the excitation/inhibition (E/I) balance toward inhibition as pyramidal neurons reach their young adult properties. The increase in inhibitory drive accompanied a protracted process of postnatal maturation of inhibitory circuits mediated by parvalbumin expressing neurons (PV ⁺ neurons) that showed an increase in their association with perineuronal nets (PNNs) as well as refinement of their connectivity onto pyramidal neurons. Together, our results indicate that GC neurons undergo protracted postnatal maturation that may influence taste response properties. Significance Statement We show that the circuit in the gustatory cortex (GC) undergoes a protracted maturation process extending into adulthood that shifts the excitability of GC toward inhibition through changes in pyramidal neurons membrane properties, increased inhibitory synaptic drive and refinement of parvalbumin neurons connectivity. GC circuit refinement extends beyond the developmental windows previously reported for other sensory cortical circuits and overlaps with the window of maturation for taste receptor cells and with the critical period for the development of taste preferences. As finding nutritious food sources may require the integration of vision, audition, somatosensation and olfaction, an extended maturation of GC may facilitate the integration of sensory information for the identification of food and the decision to ingest it.

Cortical neurons in sensory areas undergo a protracted process of postnatal maturation that includes changes in membrane properties, synaptic drive and connectivity. The completion of this process is associated with the closure of sensitive windows for experience-dependent plasticity. Weaning is a critical time in the development of taste circuits as animals transition from depending on the mother for nutrition to eating independently. While there is some evidence for developmental changes in taste bud innervation and in membrane properties of neurons in brainstem circuits for taste, very little is known about postnatal changes in the gustatory cortex (GC), the primary cortical region for taste and taste-guided behaviors. Here, we focused on pyramidal neurons in the deep layers of GC and compared their membrane properties in pre- and postweaning age groups. We report dynamic changes in intrinsic excitability and a progressive shift of the excitation/inhibition (E/I) balance toward inhibition as pyramidal neurons reach their young adult properties. The increase in inhibitory drive accompanied a protracted process of postnatal maturation of inhibitory circuits mediated by parvalbumin expressing neurons (PV neurons) that showed a progressive increase in their association with perineuronal nets (PNNs) and refinement of their connectivity onto pyramidal neurons. Together, our results indicate that GC neurons undergo protracted postnatal maturation that may influence taste response properties at the transition to independent feeding. Significance Statement: We show that the circuit in the gustatory cortex undergoes a protracted maturation process that extends into adulthood and progressively shifts the excitability of GC toward inhibition through changes in pyramidal neurons membrane properties, increased inhibitory synaptic drive and refinement of parvalbumin neurons connectivity. This maturation process extends beyond the developmental windows previously reported for other sensory cortical circuits and overlaps with the recently identified critical period for the development of taste preferences. As finding nutritious food sources may require the integration of vision, audition, somatosensation and olfaction, the extended maturation process for taste cortical circuits may facilitate the integration of sensory information for the identification of food and the decision to ingest it.

Summary: Taste preference is a fundamental driver of feeding behavior influencing dietary choices and eating patterns. Extensive experimental evidence indicates that the gustatory cortex (GC) is engaged in taste perception, palatability and preference. However, our knowledge of the neural and neurochemical signals regulating taste preference is rather limited. Neuromodulators can affect preferences, though their effects on neural circuits for taste are incompletely understood. Neurosteroids are of particular interest in view of reports that systemic administration of the neurosteroid allopregnanolone, a potent modulator of tonic GABAergic inhibition, induces hyperphagia and increases intake of energy rich food in human and animal subjects. Tonic inhibition is a powerful modulator of circuit excitability and is primarily mediated by extrasynaptic GABA _A receptors containing the delta subunit (δ-GABA _A Rs). These receptors are widely distributed in the brain, but information regarding the expression of δ-GABA _A Rs within gustatory circuits is lacking, and their role in taste preference has not been investigated. Here, we focused on GC to investigate whether activation of δ-GABA _A Rs affects sweet taste preference in adult mice. Our data reveal that δ-GABA _A Rs are expressed in multiple cell types within GC. These receptors mediate an allopregnanolone-sensitive tonic current and decrease sweet taste preference by altering the behavioral sensitivity to sucrose concentration in a cell type-specific manner. Our findings demonstrate that taste sensitivity and preference in the adult mammalian brain are modulated by tonic inhibition mediated by neurosteroid-activated δ-GABA _A Rs in GC.

Glycation, the non-enzymatic attachment of reactive dicarbonyls to proteins, lipids, or nucleic acids, contributes to the formation of advanced glycation end-products (AGEs). In Alzheimer’s disease (AD), amyloid-beta (Aβ) undergoes post-translational glycation to produce glycated Aβ (gAβ), yet its pathological role remains poorly understood. Here, we demonstrate that gAβ promotes neuronal mitochondrial DNA (mtDNA) efflux via a VDAC1-dependent mechanism, activating the innate immune cGAS-STING pathway. Using aged AD mice and human AD brain samples, we observed cGAS-mtDNA binding and cGAS-STING activation in the neuronal cytoplasm. Knockdown of RAGE, cGAS, or STING, as well as pharmacological inhibition of VDAC1, protected APP mice from mitochondrial dysfunction and Alzheimer’s-like pathology. Neuron-specific cGAS knockdown confirmed its pivotal role in driving neuroinflammation and cognitive deficits. Treatment with ALT-711, an AGE cross-link breaker, alleviated gAβ-associated pathology. Furthermore, RAGE inhibition in APP knock-in mice suppressed innate immune activation and disease-associated gene expression, as revealed by spatially resolved transcriptomics. Collectively, our findings establish a mechanistic link between gAβ and innate immune activation, identifying VDAC1, the AGE-RAGE axis, and the cGAS-STING pathway as promising therapeutic targets in AD. Significance Statement: This study reveals how a modified form of amyloid-beta disrupts mitochondrial function in neurons, triggering innate immunity and disease progression. We show that this modified amyloid-beta damages mitochondria, activating a specific immune response in the brain. By identifying the key molecules involved, we provide potential targets for new Alzheimer’s treatments aimed at preventing mitochondrial damage and cognitive decline. This research offers fresh insights into Alzheimer’s development and highlights new therapeutic pathways.

In primary gustatory cortex (GC), a subregion of the insular cortex, neurons show anticipatory activity, encode taste identity and palatability, and their activity is related to decision-making. Inactivation of the gustatory thalamus, the parvicellular region of the ventral posteromedial thalamic nucleus (VPMpc), dramatically reduces GC taste responses, consistent with the hypothesis that VPMpc-GC projections carry taste information. Recordings in awake rodents reported that taste-responsive neurons can be found across GC, without segregated spatial mapping, raising the possibility that projections from the taste thalamus may activate GC broadly. In addition, we have shown that cortical inhibition modulates the integration of thalamic and limbic inputs, revealing a potential role for GABA transmission in gating sensory information to GC. Despite this wealth of information at the system level, the synaptic organization of the VPMpc-GC circuit has not been investigated. Here, we used optogenetic activation of VPMpc afferents to GC in acute slice preparations from rats of both sexes to investigate the synaptic properties and organization of VPMpc afferents in GC and their modulation by cortical inhibition. We hypothesized that VPMpc-GC synapses are distributed across GC, but show laminar- and cell-specific properties, conferring computationally flexibility to how taste information is processed. We also found that VPMpc-GC synaptic responses are strongly modulated by the activity regimen of VPMpc afferents, as well as by cortical inhibition activating GABA _A and GABA _B receptors onto VPMpc terminals. These results provide a novel insight into the complex features of thalamocortical circuits for taste processing. SIGNIFICANCE STATEMENT We report that the input from the primary taste thalamus to the primary gustatory cortex (GC) shows distinct properties compared with primary thalamocortical synapses onto other sensory areas. Ventral posteromedial thalamic nucleus afferents in GC make synapses with excitatory neurons distributed across all cortical layers and display frequency-dependent short-term plasticity to repetitive stimulation; thus, they do not fit the classic distinction between drivers and modulators typical of other sensory thalamocortical circuits. Thalamocortical activation of GC is gated by cortical inhibition, providing local corticothalamic feedback via presynaptic ionotropic and metabotropic GABA receptors. The connectivity and inhibitory control of thalamocortical synapses in GC highlight unique features of the thalamocortical circuit for taste.

Activation of the primary motor cortex (M1) is important for the execution of skilled movements and motor learning, and its dysfunction contributes to the pathophysiology of Parkinson's disease (PD). A well-accepted idea in PD research, albeit not tested experimentally, is that the loss of midbrain dopamine leads to decreased activation of M1 by the motor thalamus. Here, we report that midbrain dopamine loss altered motor thalamus input in a laminar- and cell type-specific fashion and induced laminar-specific changes in intracortical synaptic transmission. Frequency-dependent changes in synaptic dynamics were also observed. Our results demonstrate that loss of midbrain dopaminergic neurons alters thalamocortical activation of M1 in both male and female mice, and provide novel insights into circuit mechanisms for motor cortex dysfunction in a mouse model of PD. SIGNIFICANCE STATEMENT Loss of midbrain dopamine neurons increases inhibition from the basal ganglia to the motor thalamus, suggesting that it may ultimately lead to reduced activation of primary motor cortex (M1). In contrast with this line of thinking, analysis of M1 activity in patients and animal models of Parkinson's disease report hyperactivation of this region. Our results are the first report that midbrain dopamine loss alters the input–output function of M1 through laminar and cell type specific effects. These findings support and expand on the idea that loss of midbrain dopamine reduces motor cortex activation and provide experimental evidence that reconciles reduced thalamocortical input with reports of altered activation of motor cortex in patients with Parkinson's disease.

Early experience with food influences taste preference in adulthood. How gustatory experience influences development of taste preferences and refinement of cortical circuits has not been investigated. Here, we exposed weanling mice to an array of taste solutions and determined the effects on the preference for sweet in adulthood. We demonstrate an experience-dependent shift in sucrose preference persisting several weeks following the termination of exposure. A shift in sucrose palatability, altered neural responsiveness to sucrose, and inhibitory synaptic plasticity in the gustatory portion of the insular cortex (GC) were also induced. The modulation of sweet preference occurred within a restricted developmental window, but restoration of the capacity for inhibitory plasticity in adult GC reactivated the sensitivity of sucrose preference to taste experience. Our results establish a fundamental link between gustatory experience, sweet preference, inhibitory plasticity, and cortical circuit function and highlight the importance of early life nutrition in setting taste preferences.

In the rat primary gustatory cortex (GC), a subregion of the larger insular cortex, neurons display time-varying neural responses to gustatory stimuli. GC taste responses are dramatically reduced following inactivation of the gustatory thalamus, the parvicellular region of the ventral posteromedial thalamic nucleus (VPMpc). Pharmacological inactivation of VPMpc also has a profound effect on GC spontaneous activity. This indicates that the projection from VPMpc plays a crucial role in GC taste processing as well as in the control of its state. How VPMpc afferents engage GC circuits and drive neuronal ensembles to effectively code tastant identity, as well as modulate the overall state of the GC network, remains unclear. To investigate the synaptic properties and organization of VPMpc afferents in GC, we employed a circuit-breaking optogenetic approach, stimulating VPMpc terminal fields while performing whole-cell patch clamp recordings from GC neurons in rat acute slices. Informed by previous studies of thalamocortical inputs to other sensory cortices, we hypothesized that VPMpc-GC synapses have laminar- and cell-specific properties that gate sensory input, conferring computationally flexibility to how taste information is processed in GC. We found that VPMpc-GC synapses are strongly gated by the activity regime of VPMpc afferents, as well as by feedforward and feedback inhibition onto VPMpc terminals. These results provide novel insight into the circuit underpinning of GC responsiveness to incoming thalamocortical activity. SIGNIFICANCE STATEMENT: We report that the input from the primary taste thalamus to the primary gustatory cortex (GC) shows distinct properties compared to primary thalamocortical synapses onto other sensory areas. VPMpc afferents in GC make synapses with excitatory neurons distributed across all cortical layers and display frequency-dependent short-term plasticity to repetitive stimulation, thus they do not fit the classic distinction between drivers and modulators typical of other sensory thalamocortical circuits. Feedforward inhibition gates thalamocortical activation and provides local corticothalamic feedback via presynaptic ionotropic and metabotropic GABA receptors. The connectivity and inhibitory control of thalamocortical synapses support the time-varying response dynamics to taste stimuli observed in GC neurons in vivo .