Biology subjects

Maffei, A.

Publications and source records attributed to Maffei, A..

9 recordsLinked to original sources

bioRxiv2025

Postnatal development of pyramidal neurons excitability and synaptic inputs in mouse gustatory cortical circuits

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 StatementWe 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.

neuroscience↗

bioRxiv2024

Modulation of sweet preference by neurosteroid-sensitive, δ-GABAA receptors in adult mouse gustatory insular cortex

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 GABAA receptors containing the delta subunit ({delta}-GABAARs). These receptors are widely distributed in the brain, but information regarding the expression of {delta}-GABAARs 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 {delta}-GABAARs affects sweet taste preference in adult mice. Our data reveal that {delta}-GABAARs 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 {delta}-GABAARs in GC.

neuroscience↗

bioRxiv2024

Amyloid beta glycation leads to neuronal mitochondrial dysfunction and Alzheimers pathogenesis through VDAC1-dependent mtDNA efflux

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 Alzheimers disease (AD), amyloid-beta (A{beta}) undergoes post-translational glycation to produce glycated A{beta} (gA{beta}), yet its pathological role remains poorly understood. Here, we demonstrate that gA{beta} 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 Alzheimers-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 gA{beta}-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 gA{beta} and innate immune activation, identifying VDAC1, the AGE-RAGE axis, and the cGAS-STING pathway as promising therapeutic targets in AD. Significance StatementThis 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 Alzheimers treatments aimed at preventing mitochondrial damage and cognitive decline. This research offers fresh insights into Alzheimers development and highlights new therapeutic pathways.

neuroscience↗

bioRxiv2022

Inhibitory gating of thalamocortical inputs onto rat gustatory insular cortex

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 STATEMENTWe 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.

neuroscience↗

bioRxiv2022

Experience-dependent plasticity of gustatory insular cortex circuits and taste preferences

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 tastants 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 experience in setting taste preferences.

neuroscience↗

bioRxiv2020

Altered Thalamocortical Signaling in a Mouse Model of Parkinson's Disease

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 Parkinsons disease (PD). A well accepted idea in PD research, albeit not tested experimentally, is that loss of midbrain dopamine leads to decreased activation of M1 by the motor thalamus (Mthal). Here, we report that midbrain dopamine loss reduced Mthal input in a laminar- and cell type-specific fashion and induced laminar-specific changes in intracortical synaptic transmission. As a result, M1 activation by Mthal was decreased, but M1 output was increased. Our results demonstrate that loss of midbrain dopaminergic neurons alters thalamocortical activation of M1, and provide novel insights into circuit mechanisms for motor cortex dysfunction in a mouse model of PD.

neuroscience↗

bioRxiv2020

Event-related network changes unfold the dynamics of cortical integration during face processing

Face perception arises from a collective activation of brain regions in the occipital, parietal and temporal cortices. Despite wide acknowledgement that these regions act in an intertwined network, the network behavior itself is poorly understood. Here we present a study in which time-varying connectivity estimated from EEG activity elicited by facial expressions presentation was characterized using graph-theoretical measures of node centrality and global network topology. Results revealed that face perception results from a dynamic reshaping of the network architecture, characterized by the emergence of hubs located in the occipital and temporal regions of the scalp. The importance of these nodes can be observed from early stages of visual processing and reaches a climax in the same time-window in which the face-sensitive N170 is observed. Furthermore, using Granger causality, we found that the time-evolving centrality of these nodes is associated with ERP amplitude, providing a direct link between the network state and local neural response. Additionally, investigating global network topology by means of small-worldness and modularity, we found that face processing requires a functional network with a strong small-world organization that maximizes integration, at the cost of segregated subdivisions. Interestingly, we found that this architecture is not static, but instead it is implemented by the network from stimulus onset to ~200 msec. Altogether, this study reveals the event-related changes underlying face processing at the network level, suggesting that a distributed processing mechanism operates through dynamically weighting the contribution of the cortical regions involved. Data AvailabilityData and code related to this manuscript can be accessed through the OSF at this link https://osf.io/hc3sk/?view_only=af52bc4295c044ffbbd3be019cc083f4

neuroscience↗

bioRxiv2020

Reduced dopamine signaling impacts pyramidal neuron excitability in mouse motor cortex

Dopaminergic modulation is essential for the control of voluntary movement, however the role of dopamine in regulating the neural excitability of the primary motor cortex (M1) is not well understood. Here, we investigated two modes by which dopamine influences the input/output function of M1 neurons. To test the direct regulation of M1 neurons by dopamine, we performed whole-cell recordings of excitatory neurons and measured excitability before and after local, acute dopamine receptor blockade. We then determined if chronic depletion of dopaminergic input to the entire motor circuit, through a mouse model of Parkinsons Disease, was sufficient to shift M1 neuron excitability. We show that D1 and D2 receptor (D1R, D2R) antagonism altered subthreshold and suprathreshold properties of M1 pyramidal neurons in a layer-specific fashion. The effects of D1R antagonism were primarily driven by changes to intrinsic properties, while the excitability shifts following D2R antagonism relied on synaptic transmission. In contrast, chronic depletion of dopamine to the motor circuit with 6-hydroxydopamine (6OHDA) induced layer-specific synaptic transmission-dependent shifts in M1 neuron excitability that only partially overlapped with the effects of acute D1R antagonism. These results suggest that while acute and chronic changes in dopamine modulate the input/output function of M1 neurons, the mechanisms engaged are distinct depending on the duration and location of the manipulation. Our study highlights dopamines broad influence on M1 excitability by demonstrating the consequences of local and global dopamine depletion on neuronal input/output function. Significance statementDopaminergic signaling is crucial for the control of voluntary movement, and loss of dopaminergic transmission in the motor circuit is thought to underlie motor symptoms in those with Parkinsons Disease (PD). Studies in animal models of PD highlight changes in M1 activity following dopamine depletion, however the mechanisms underlying this phenomenon remain poorly understood. Here we show that diminished dopamine signaling significantly alters the excitability and input/output function of M1 pyramidal neurons. The effects differed depending on the mode and location - local versus across the motor pathway - of the dopamine manipulation. Our results demonstrate how loss of dopamine can engage complex mechanisms to alter M1 neurons activity.

neuroscience↗

bioRxiv2019

LTD at amygdalocortical synapses as a novel mechanism for hedonic learning

A novel, pleasant taste stimulus becomes aversive if associated with gastric malaise, a form of learning known as conditioned taste aversion (CTA). CTA is common to vertebrates and invertebrates and is an important survival response: eating the wrong food may be deadly. CTA depends on the gustatory portion of the insular cortex (GC) and the basolateral nucleus of the amygdala (BLA) however, its synaptic underpinnings are unknown. Here we report that CTA was associated with decreased expression of immediate early genes in rat GC of both sexes, and with reduced amplitude of BLA-GC synaptic responses, pointing to long term depression (LTD) as a mechanism for learning. Indeed, association of a novel tastant with induction of LTD at the BLA-GC input in vivo was sufficient to change the hedonic value of a taste stimulus. Our results demonstrate a direct role for amygdalocortical LTD in taste aversion learning.

neuroscience↗