Cortical areas comprise multiple types of inhibitory interneurons, with stereotypical connectivity motifs that may follow specific plasticity rules. Yet, their combined effect on postsynaptic dynamics has been largely unexplored. Here, we analyse the response of a single postsynaptic model neuron receiving tuned excitatory connections alongside inhibition from two plastic populations. Synapses from each inhibitory population change according to distinct plasticity rules. We tested different combinations of three rules: Hebbian, anti-Hebbian and homeostatic scaling. Depending on the inhibitory plasticity rule, synapses become unspecific (flat), anti-correlated to, or correlated with excitatory synapses. Crucially, the neuron’s receptive field, i.e., its response to presynaptic stimuli, depends on the modulatory state of inhibition. When both inhibitory populations are active, inhibition balances excitation, resulting in uncorrelated postsynaptic responses regardless of the inhibitory tuning profiles. Modula...

Functional specialisation and plasticity are fundamental organising principles of the brain. Since the mid-1800s, certain cognitive functions have been known to be lateralised, but the provenance and flexibility of hemispheric specialisation remain open questions. Language is a uniquely human phenomenon that requires a delicate balance between neural specialisation and plasticity, and language learning offers the perfect window to study these principles in the human brain. In the current study, we conducted two separate functional MRI experiments with male and female language learners, one cross-sectional and one longitudinal, involving distinct populations and languages, and examined hemispheric lateralisation and learning-dependent plasticity of three language systems: reading, speech comprehension and verbal production. A multi-pronged analytic approach revealed a highly consistent pattern of results across the two experiments, showing that (i) in both native and non-native languages, while language pro...

Single cell analysis is revealing increasing diversity in gene expression profiles among brain cells. Traditional promotor-based viral gene expression techniques, however, cannot capture the growing variety among single cells. We demonstrate a novel viral gene expression strategy to target cells with specific microRNA expression using microRNA-guided neuron tags (mAGNET). We designed mAGNET viral vectors containing a CamKIIα-promoter and miR-128 binding sets, and labeled CamKIIα-positive cells with naturally low expression of miR-128 (Lm128C cells) in male and female mice. Even though CamKIIα has traditionally been considered as an excitatory neuron marker, our single cell sequencing results reveal that Lm128C cells are CamKIIα positive inhibitory neurons of parvalbumin or somatostatin subtypes. Further evaluation of the physiological properties of Lm128C cell in brain slices showed that Lm128C cells exhibit elevated membrane excitability with biophysical properties closely resembling those of fast-spiking...

Autism spectrum disorder (ASD) is characterized by a core deficit in theory-of-mind (ToM) ability, which extends to perturbations in moral judgment and decision-making. Although the function of the right temporoparietal junction (rTPJ), a key neural marker of ToM and morality, is known to be altered in autistic individuals, the neurocomputational mechanisms underlying its specific impairment in moral decision-making remain unclear. Here, we addressed this question by employing a novel fMRI task together with computational modeling and representational similarity analysis (RSA). ASD patients and healthy controls (HC) decided in public or private whether to incur a personal cost for funding a morally-good cause (Good Context) or receive a personal gain for benefiting a morally-bad cause (Bad Context). Compared with HC, individuals with ASD were much more likely to reject the opportunity to earn ill-gotten money by supporting a bad cause than HC. Computational modeling revealed that this resulted from unduly ...

Selective visual attention allows the brain to focus on behaviorally relevant information while ignoring irrelevant signals. As a possible mechanism, routing-by-synchronization was proposed: neural populations receiving attended signals align their gamma-rhythmic activity to that of the sending populations, such that incoming spikes arrive at excitability peaks of receiving populations, enhancing signal transfer. Conversely, non-attended signals arrive unaligned to the receiver's oscillation, reducing signal transfer. Therefore, visual signals should be transferred through gamma-rhythmic bursts of information, resulting in a modulation of the stimulus content within the receiving population’s activity by its gamma phase and amplitude. To test this prediction, we quantified gamma phase-dependent stimulus content within neural activity from area V4 of two male macaques performing a visual attention task. For the attended stimulus, we find highest stimulus information content near excitability peaks, an effec...

Models of memory formation posit that episodic memory formation depends critically on the hippocampus, which binds features of an event to its context. For this reason, the contrast between study items that are later recollected with their associative pair versus those for which no association is made fails should reveal electrophysiological patterns in the hippocampus selectively involved in associative memory encoding. Extensive data from studies in rodents support a model in which theta oscillations fulfill this role, but results in humans have not been as clear. Here, we employed an associative recognition memory procedure to identify hippocampal correlates of successful associative memory encoding and retrieval in patients (10 females and 9 males) undergoing intracranial EEG monitoring. We identified a dissociation between 2-5 Hz and 5-9 Hz theta oscillations, by which power increases in 2-5 Hz oscillations were uniquely linked with successful associative memory in both the anterior and posterior hipp...

Expression of the 17β-estradiol (E2) synthesis enzyme aromatase, is highly upregulated in astrocytes following brain injury. However, the precise role of astrocyte-derived E2 in the injured brain remains unclear. In the current study, we generated a GFAP promoter-driven aromatase knockout (GFAP-ARO-KO) mouse model to deplete astrocyte-derived E2 in the brain and determine its roles after global cerebral ischemia (GCI) in male and female mice. GFAP-ARO-KO mice were viable and fertile, with normal gross brain structure, normal morphology, intensity and distribution of astrocytes, normal aromatase expression in neurons, and normal cognitive function basally. In contrast, after GCI, GFAP-ARO-KO mice: 1) lacked the normal elevation of astrocyte aromatase and hippocampal E2 levels, 2) had significantly attenuated reactive astrogliosis, and 3) displayed enhanced neuronal damage, microglia activation, and cognitive deficits. RNA-seq analysis revealed that the ischemic GFAP-ARO-KO mouse hippocampus failed to upregu...

Neurobehavioral studies in humans have long concentrated on changes in local activity levels during repetitive executions of a task. Spontaneous neural coupling within extended networks has latterly been found to also influence performance. Here, we intend to uncover the underlying mechanisms, the relative importance and the interaction between spontaneous coupling and task-induced activations. To do so, we recorded two groups of healthy participants (male and female) during rest and while they performed either a visual perception or a motor sequence task. We demonstrate that for both tasks, stronger activations during the task as well as greater network coupling through spontaneous alpha rhythms at rest predict performance. However, high performers present an absence of classical task-induced activations, and, instead, stronger spontaneous network coupling. Activations were thus a compensation mechanism needed only in subjects with lower spontaneous network interactions. This challenges classical models o...

d-serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic d-serine remains limited. Though early studies suggested d-serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and d-serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons. In addition, using a single-neuron genetic approach in SR conditional knockout mice from both sexes, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Import...

Functional recovery in the end target muscle is a determinant of outcome after peripheral nerve injury. The neuromuscular junction (NMJ) provides the interface between nerve and muscle and includes nonmyelinating terminal Schwann cells (tSCs). After nerve injury, tSCs extend cytoplasmic processes between NMJs to guide axon growth and NMJ reinnervation. The mechanisms related to NMJ reinnervation are not known. We utilized multiple mouse models to investigate the mechanisms of NMJ reinnervation in both sexes, specifically whether macrophage-derived Vascular Endothelial Growth Factor-A (Vegf-A) is crucial to establishing NMJ reinnervation at the end target muscle. Both macrophage number and Vegf-A expression increased in end target muscles after nerve injury and repair. In mice with impaired recruitment of macrophages and monocytes ( Ccr2-/- mice ), the absence of CD68+ cells (macrophages) in the muscle resulted in diminished muscle function. Using a Vegf-Receptor 2 inhibitor (Cabozantinib) via oral gavage i...