Biology subjects

Locarno, A.

Publications and source records attributed to Locarno, A..

4 recordsLinked to original sources

bioRxiv2026

Cellular and Network Effects of Introducing Connexin-36 Expression in an Uncoupled Neuronal Population in the Mouse Hypothalamus

Electrical synapses are prevalent throughout nervous systems, including the mammalian brain. Several lines of evidence implicate these gap junction connections in several important roles in neural networks. Yet, progress has been hampered by a shortage of experimental tools to investigate their function with sufficient precision. In an effort to address this deficit, we here take advantage of a curious species-difference in electrical coupling in tuberoinfundibular dopamine (TIDA) neurons of the rodent hypothalamus. In rats, these cells exhibit strong electrical coupling, generating stereotyped, slow oscillations that are synchronized across the population. In contrast, mouse TIDA neurons lack gap junctions and display diverse, faster, and asynchronous oscillations. Motivated by this natural discrepancy, we designed a gain-of-function strategy to induce localized and robust expression of the main pore-forming protein of neuronal gap junctions, connexin-36 (Cx36), in mouse TIDA neurons by viral vectors. This perturbation yielded electrical coupling that was weaker than the rat TIDA system, but on par with many other brain populations connected by gap junctions. Cx36 overexpression resulted in significantly increased auto- and cross-correlation, as well as augmented functional connectivity, in agreement with the induction of electrical synapses in the population. Yet, these measures were modest in comparison with rat TIDA neurons, and Cx36 overexpression failed to alter serum levels of the hormone prolactin, which is controlled by this neuroendocrine system. These findings highlight the potential and limitations of experimentally inducing electrical synapses in a natively uncoupled system, and suggest directions for future improvements.

neuroscience↗

bioRxiv2026

Stable Network Homeostasis during Multi-Level Postnatal Maturation of the Mouse Tuberoinfundibular Dopamine-Prolactin Axis

The hypothalamus orchestrates endocrine function via specialized neuronal populations that interface with the pituitary gland. While postnatal circuit refinement is a hallmark of most neural systems, its contribution to hypothalamic neuroendocrine networks remains elusive. Among these populations, tuberoin-fundibular dopamine (TIDA) neurons of the arcuate nucleus are the primary source of tonic inhibition of prolactin (Prl), a hormone essential for reproduction, parental physiology, and behavior. While Prl levels surge during early mouse postnatal life, it remains unclear whether the TIDA system is fully developed at birth or undergoes functional maturation. Here, we combined immunofluorescence, slice electrophysiology, and Ca2+ imaging to determine the development of TIDA neurons in mice during the first three postnatal weeks. Expression of dopaminergic markers was sparse at birth but rose substantially after the first week, followed by the onset of median eminence innervation by TIDA axons. Moreover, TIDA firing rate and oscillation frequency progressively increased with age, with action potential properties and rhythmicity maturing in tandem. Strikingly, local network parameters remained stable despite ongoing changes in single-cell properties, as did excitation/inhibition (E/I) balance. These neuronal adaptations paralleled a significant rise in circulating Prl levels. Together, our results delineate a multi-level developmental program within the TIDA system, encompassing molecular, electrophysiological, and endocrine changes. This maturation likely underlies the emergence of functional hypothalamic control over Prl secretion in early life and points to a coordinated controller-effector co-development. Our findings highlight a critical window during which TIDA neuron plasticity may influence long-term neuroendocrine function and reproductive behavior. Significance StatementUnderstanding how neuroendocrine circuits mature is critical for elucidating the developmental origins of hormonal homeostatic control. We reveal that tuberoinfundibular dopamine (TIDA) neurons, which control reproduction by inhibiting the release of the pituitary hormone, prolactin (Prl), undergo a tightly orchestrated postnatal maturation program encompassing population expansion, electrophysiological refinement, and synaptic scaling. Surprisingly, although individual cellular features undergo substantial shifts, network behavior remains remarkably consistent, in parallel with a gradual rise in Prl. This multi-level developmental sequence likely enables the gradual assembly of a functional TIDA-Prl axis. By defining the timeline of TIDA circuit maturation, our work provides a framework for exploring how early-life perturbations may disrupt neuroendocrine development and lead to lifelong alterations in reproductive and parental behaviors.

neuroscience↗

bioRxiv2026

Cortical Layer 6b Persistent Subplate Neurons Reciprocally Connect Sensorimotor Areas and Inversely Reflect Somatosensory Engagement

Persistent subplate neurons in layer 6b (L6b) of the cerebral cortex have long been assumed to be a passive remnant of early development. Recent findings are challenging this concept, but the functional role of L6b remains mysterious. A large group of L6b neurons express Connective Tissue Growth Factor (Ctgf). Here, we mapped L6bCtgf neurons throughout the cortex and found the highest density in primary sensorimotor areas. Cortical L6bCtgf projections are ipsilaterally restricted and origin-site specific, with notable reciprocity, whereas innervation of the thalamus is modality-matched. L6bCtgf neurons are electrically diverse and form excitatory synapses with both pyramidal cells and interneurons. In freely moving mice, these neurons are highly active and have prominent task-specific and temporally locked responses to external stimuli. These responses are dominated by paradoxical population silencing with escalating task engagement. Thus, L6bCtgf neurons may keep cortical ensembles in a state of alertness and available to process cognate stimuli. HIGHLIGHTSO_LIL6bCtgf neurons form origin-and layer-specific ipsilateral cortical connections. C_LIO_LIElectrically heterogeneous L6bCtgf neurons excite multiple classes of cortical neurons. C_LIO_LIBarrel cortex L6bCtgf neurons are highly active in freely moving mice. C_LIO_LISomatosensory exploration paradoxically silences active barrel cortex L6bCtgf neurons. C_LI

neuroscience↗

bioRxiv2020

A cross-species link between mTOR-related synaptic pathology and functional hyperconnectivityin autism

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism, with a putative link to aberrant mTOR-dependent synaptic pruning. Autism is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses cause aberrant functional connectivity in autism. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with autism-like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic autism exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for autism-dysregulated genes interacting with mTOR or TSC2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism. SignificanceAberrant brain functional connectivity is a hallmark of autism, but the neural basis of this phenomenon remains unclear. We show that a mouse line recapitulating mTOR-dependent synaptic pruning deficits observed in postmortem autistic brains exhibits widespread functional hyperconnectivity. Importantly, pharmacological normalization of mTOR signalling completely rescues synaptic, behavioral and functional connectivity deficits. We also show that a similar connectivity fingerprint can be isolated in human fMRI scans of people with autism, where it is linked to over-expression of mTOR-related genes. Our results reveal a unifying multi-scale translational framework that mechanistically links aberrations in synaptic pruning with functional hyperconnectivity in autism.

neuroscience↗