Atypical cadherin, Fat2, regulates axon terminal organization in the developing Drosophila olfactory receptor neurons.

The process of how neuronal identity confers circuit organization is intricately related to the mechanisms underlying neurodegeneration and neuropathologies. Modeling this process, the olfactory circuit builds a functionally organized topographic map, which requires widely dispersed neurons with the same identity to converge their axons into one a class-specific neuropil, a glomerulus. In this article, we identified Fat2 (also known as Kugelei) as a regulator of class-specific axon organization. In fat2 mutants, axons belonging to the highest fat2-expressing classes present with a more severe phenotype compared to axons belonging to low fat2-expressing classes. In extreme cases, mutations lead to neural degeneration. Lastly, we found that Fat2 intracellular domain interactors, APC1/2 (Adenomatous polyposis coli) and dop (Drop out), likely orchestrate the cytoskeletal remodeling required for axon condensation. Altogether, we provide a potential mechanism for how cell surface proteins' regulation of cytoskeletal remodeling necessitates identity specific circuit organization.

Lateralized modulation of cortical beta power during human gait is related to arm swing.

Human gait is a complex behavior requiring dynamic control of upper and lower extremities that is accompanied by cortical activity in multiple brain areas. We investigated the contribution of beta (15-30 Hz) and gamma (30-50 Hz) band electroencephalography (EEG) activity during specific phases of the gait cycle, comparing treadmill walking with and without arm swing. Modulations of spectral power in the beta band during early double support and swing phases source-localized to the sensorimotor cortex ipsilateral, but not contralateral, to the leading leg. The lateralization disappeared in the condition with constrained arms, together with an increase of activity in bilateral supplementary motor areas. By contrast, gamma band modulations that localized to the presumed leg area of sensorimotor cortex around the heel-strike events were unaffected by arm movement. Our findings demonstrate that arm swing is accompanied by considerable cortical activation that should not be neglected in gait-related neuroimaging studies.

Mitochondrial transfer between BMSCs and Müller promotes mitochondrial fusion and suppresses gliosis in degenerative retina.

Mitochondrial dysfunction and Müller cells gliosis are significant pathological characteristics of retinal degeneration (RD) and causing blinding. Stem cell therapy is a promising treatment for RD, the recently accepted therapeutic mechanism is cell fusion induced materials transfer. However, whether materials including mitochondrial transfer between grafted stem cells and recipient's cells contribute to suppressing gliosis and mechanism are unclear. In present study, we demonstrated that bone marrow mesenchymal stem cells (BMSCs) transferred mitochondria to Müller cells by cell fusion and tunneling nanotubes. BMSCs-derived mitochondria (BMSCs-mito) were integrated into mitochondrial network of Müller cells, improving mitochondrial function, reducing oxidative stress and gliosis, which protected visual function partially in the degenerative rat retina. RNA sequencing analysis revealed that BMSCs-mito increased mitochondrial DNA (mtDNA) content and facilitated mitochondrial fusion in damaged Müller cells. It suggests that mitochondrial transfer from BMSCs remodels Müller cells metabolism and suppresses gliosis; thus, delaying the degenerative progression of RD.

Altered neuronal lactate dehydrogenase A expression affects cognition in a sex- and age-dependent manner.

The astrocyte-neuron lactate shuttle (ANLS) model posits that astrocyte-generated lactate is transported to neurons to fuel memory processes. However, neurons express high levels of lactate dehydrogenase A (LDHA), the rate-limiting enzyme of lactate production, suggesting a cognitive role for neuronally generated lactate. It was hypothesized that lactate metabolism in neurons is critical for learning and memory. Here transgenic mice were generated to conditionally induce or knockout (KO) the Ldha gene in CNS neurons of adult mice. High pattern separation memory was enhanced by neuronal Ldha induction in young females, and by neuronal Ldha KO in aged females. In older mice, Ldha induction caused cognitive deficits whereas Ldha KO caused cognitive improvements. Genotype-associated cognitive changes were often only observed in one sex or oppositely in males and females. Thus, neuronal-generated lactate has sex-specific cognitive effects, is largely indispensable at young age, and may be detrimental to learning and memory with aging.

Thalamocortical interactions shape hierarchical neural variability during stimulus perception.

The brain is organized hierarchically to process sensory signals. But, how do functional connections within and across areas contribute to this hierarchical order? We addressed this problem in the thalamocortical network, while monkeys detected vibrotactile stimulus. During this task, we quantified neural variability and directed functional connectivity in simultaneously recorded neurons sharing the cutaneous receptive field within and across VPL and areas 3b and 1. Before stimulus onset, VPL and area 3b exhibited similar fast dynamics while area 1 showed slower timescales. During the stimulus presence, inter-trial neural variability increased along the network VPL-3b-1 while VPL established two main feedforward pathways with areas 3b and 1 to process the stimulus. This lower variability of VPL and area 3b was found to regulate feedforward thalamocortical pathways. Instead, intra-cortical interactions were only anticipated by higher intrinsic timescales in area 1. Overall, our results provide evidence of hierarchical functional roles along the thalamocortical network.

Laminar dissociation of feedforward and feedback in high-level ventral visual cortex during imagery and perception.

Visual imagery and perception share neural machinery but rely on different information flow. While perception is driven by the integration of sensory feedforward and internally generated feedback information, imagery relies on feedback only. This suggests that although imagery and perception may activate overlapping brain regions, they do so in informationally distinctive ways. Using lamina-resolved MRI at 7 T, we measured the neural activity during imagery and perception of faces and scenes in high-level ventral visual cortex at the mesoscale of laminar organization that distinguishes feedforward from feedback signals. We found distinctive laminar profiles for imagery and perception of scenes and faces in the parahippocampal place area and the fusiform face area, respectively. Our findings provide insight into the neural basis of the phenomenology of visual imagery versus perception and shed new light into the mesoscale organization of feedforward and feedback information flow in high-level ventral visual cortex.

Layer specific regulation of critical period timing and maturation of mouse visual cortex by endocannabinoids.

Plasticity during the critical period is important for the functional maturation of cortical neurons. While characteristics of plasticity are diverse among cortical layers, it is unknown whether critical period timing is controlled by a common or unique molecular mechanism among them. We here clarified layer-specific regulation of the critical period timing of ocular dominance plasticity in the primary visual cortex. Mice lacking the endocannabinoid synthesis enzyme diacylglycerol lipase-α exhibited precocious critical period timing, earlier maturation of inhibitory synaptic function in layers 2/3 and 4, and impaired development of the binocular matching of orientation selectivity exclusively in layer 2/3. Activation of cannabinoid receptor restored ocular dominance plasticity at the normal critical period in layer 2/3. Suppression of GABAA receptor rescued precocious ocular dominance plasticity in layer 4. Therefore, endocannabinoids regulate critical period timing and maturation of visual function partly through the development of inhibitory synaptic functions in a layer-dependent manner.

Hyperactive mTORC1 disrupts habenula function and light preference in zebrafish model of Tuberous sclerosis complex.

Mechanistic target of rapamycin complex 1 (mTORC1) is an integration hub for extracellular and intracellular signals necessary for brain development. Hyperactive mTORC1 is found in autism spectrum disorder (ASD) characterized by atypical reactivity to sensory stimuli, among other symptoms. In Tuberous sclerosis complex (TSC) inactivating mutations in the TSC1 or TSC2 genes result in hyperactivation of the mTORC1 pathway and ASD. Here, we show that lack of light preference of the TSC zebrafish model, tsc2 vu242/vu242 is caused by aberrant processing of light stimuli in the left dorsal habenula and tsc2 vu242/vu242 fish have impaired function of the left dorsal habenula, in which neurons exhibited higher activity and lacked habituation to the light stimuli. These characteristics were rescued by rapamycin. We thus discovered that hyperactive mTorC1 caused aberrant habenula function resulting in lack of light preference. Our results suggest that mTORC1 hyperactivity contributes to atypical reactivity to sensory stimuli in ASD.

Gap junctions fine-tune ganglion cell signals to equalize response kinetics within a given electrically coupled array.

Retinal ganglion cells (RGCs) summate inputs and forward a spike train code to the brain in the form of either maintained spiking (sustained) or a quickly decaying brief spike burst (transient). We report diverse response transience values across the RGC population and, contrary to the conventional transient/sustained scheme, responses with intermediary characteristics are the most abundant. Pharmacological tests showed that besides GABAergic inhibition, gap junction (GJ)-mediated excitation also plays a pivotal role in shaping response transience and thus visual coding. More precisely GJs connecting RGCs to nearby amacrine and RGCs play a defining role in the process. These GJs equalize kinetic features, including the response transience of transient OFF alpha (tOFFα) RGCs across a coupled array. We propose that GJs in other coupled neuron ensembles in the brain are also critical in the harmonization of response kinetics to enhance the population code and suit a corresponding task.

Transformation of spatial representations along hippocampal circuits.

The hippocampus is thought to provide the brain with a cognitive map of the external world by processing various types of spatial information. To understand how essential spatial variables such as direction, position, and distance are transformed along its circuits to construct this global map, we perform single-photon widefield microendoscope calcium imaging in the dentate gyrus and CA3 of mice freely navigating along a narrow corridor. We find that spatial activity maps in the dentate gyrus, but not in CA3, are correlated after aligning them to the running directions, suggesting that they represent the distance traveled along the track in egocentric coordinates. Together with population activity decoding, our data suggest that while spatial representations in the dentate gyrus and CA3 are anchored in both egocentric and allocentric coordinates, egocentric distance coding is more prevalent in the dentate gyrus than in CA3, providing insights into the assembly of the cognitive map.

A role for the dorsolateral striatum in prospective action control.

The dorsolateral striatum (DLS) is important for performing actions persistently, even when it becomes suboptimal, reflecting a function that is reflexive and habitual. However, there are also ways in which persistent behaviors can result from a more prospective, planning mode of behavior. To help tease apart these possibilities for DLS function, we trained animals to perform a lever press for reward and then inhibited the DLS in key test phases: as the task shifted from a 1-press to a 3-press rule (upshift), as the task was maintained, as the task shifted back to the one-press rule (downshift), and when rewards came independent of pressing. During DLS inhibition, animals always favored their initially learned strategy to press just once, particularly so during the free-reward period. DLS inhibition surprisingly changed performance speed bidirectionally depending on the task shifts. DLS inhibition thus encouraged habitual behavior, suggesting it could normally help adapt to changing conditions.

Neuronal response of the primate striatum tail to face of socially familiar persons.

Recent studies have suggested that the basal ganglia, the center of stimulus-reward associative learning, are involved in social behavior. However, the role of the basal ganglia in social information processing remains unclear. Here, we demonstrate that the striatum tail (STRt) in macaque monkeys, which is sensitive to visual objects with long-term reward history (i.e., stable object value), is also sensitive to socially familiar persons. Many STRt neurons responded to face images of persons, especially those who took daily care of the subject monkeys. These face-responsive neurons also encoded stable object value. The strength of the neuronal modulation of social familiarity and stable object value biases were positively correlated. These results suggest that both social familiarity and stable object value information are mediated by a common neuronal mechanism. Thus, the representation of social information is linked to reward information in the STRt, not in the dedicated social information circuit.

Interacting ventral temporal gradients of timescales and functional connectivity and their relationships to visual behavior.

Cortical gradients in endogenous and stimulus-evoked neurodynamic timescales, and long-range cortical interactions, provide organizational constraints to the brain and influence neural populations' roles in cognition. It is unclear how these functional gradients interrelate and which influence behavior. Here, intracranial recordings from 4,090 electrode contacts in 35 individuals map gradients of neural timescales and functional connectivity to assess their interactions along category-selective ventral temporal cortex. Endogenous and stimulus-evoked information processing timescales were not significantly correlated with one another suggesting that local neural timescales are context dependent and may arise through distinct neurophysiological mechanisms. Endogenous neural timescales correlated with functional connectivity even after removing the effects of shared anatomical gradients. Neural timescales and functional connectivity correlated with how strongly a population's activity predicted behavior in a simple visual task. These results suggest both interrelated and distinct neurophysiological processes give rise to different functional connectivity and neural timescale gradients, which together influence behavior.

Variations in touch representation in the hummingbird and zebra finch forebrain.

Somatosensation is essential for animals to perceive the external world through touch, allowing them to detect physical contact, temperature, pain, and body position. Studies on rodent vibrissae have highlighted the organization and processing in mammalian somatosensory pathways.1,2 Comparative research across vertebrates is vital for understanding evolutionary influences and ecological specialization on somatosensory systems. Birds, with their diverse morphologies, sensory abilities, and behaviors, serve as ideal models for investigating the evolution of somatosensation. Prior studies have uncovered tactile-responsive areas within the avian telencephalon, particularly in pigeons,3,4,5,6 parrots,7 and finches,8 but variations in somatosensory maps and responses across avian species are not fully understood. This study aims to explore somatotopic organization and neural coding in the telencephalon of Anna's hummingbirds (Calypte anna) and zebra finches (Taeniopygia guttata) by using in vivo extracellular electrophysiology to record activity in response to controlled tactile stimuli on various body regions. These findings reveal unique representations of body regions across distinct forebrain somatosensory nuclei, indicating significant differences in the extent of areas dedicated to certain body surfaces, which may correlate with their behavioral importance.

The relativity of reaching: Motion of the touched surface alters the trajectory of hand movements.

For dexterous control of the hand, humans integrate sensory information and prior knowledge regarding their bodies and the world. We studied the role of touch in hand motor control by challenging a fundamental prior assumption-that self-motion of inanimate objects is unlikely upon contact. In a reaching task, participants slid their fingertips across a robotic interface, with their hand hidden from sight. Unbeknownst to the participants, the robotic interface remained static, followed hand movement, or moved in opposition to it. We considered two hypotheses. Either participants were able to account for surface motion or, if the stationarity assumption held, they would integrate the biased tactile cues and proprioception. Motor errors consistent with the latter hypothesis were observed. The role of visual feedback, tactile sensitivity, and friction was also investigated. Our study carries profound implications for human-machine collaboration in a world where objects may no longer conform to the stationarity assumption.

Distinct rich and diverse clubs regulate coarse and fine binocular disparity processing: Evidence from stereoscopic task-based fMRI.

While cortical regions involved in processing binocular disparities have been studied extensively, little is known on how the human visual system adapts to changing disparity magnitudes. In this paper, we investigate causal mechanisms of coarse and fine binocular disparity processing using fMRI with a clinically validated, custom anaglyph-based stimulus. We make use of Granger causality and graph measures to reveal the existence of distinct rich and diverse clubs across different disparity magnitudes. We demonstrate that Middle Temporal area (MT) plays a specialized role with overlapping rich and diverse characteristics. Next, we show that subtle interhemispheric differences exist across various brain regions, despite an overall right hemisphere dominance. Finally, we pass the graph measures through the decision tree and found that the diverse clubs outperform rich clubs in decoding disparity magnitudes. Our study sets the stage for conducting further investigations on binocular disparity processing, particularly in the context of neuro-ophthalmic disorders with binocular impairments.

Stereo-anomaly is found more frequently in tasks that require discrimination between depths.

Within the population of humans with otherwise normal vision, there exists some proportion whose ability to perceive depth from binocular disparity is poor or absent. The prevalence of this "stereo-anomaly" has been reported to be as small as 2%, or as great as 30%. We set out to investigate this discrepancy. We used a digital tool to measure stereoacuity in tasks requiring either the detection of disparity or the discrimination of the direction of disparity. In a cohort of 228 participants, we found that 98% were able to consistently perform the detection task. Of these, only 69% consistently performed the discrimination task. The 31% of participants who had difficulty with the discrimination task could further be divided into 17% who were consistently unable to perform the task and 14% who showed limited ability. This suggests that identification of the direction of disparity requires further processing beyond merely detecting its presence.

Non-canonical type 1 cannabinoid receptor signaling regulates night visual processing in the inner rat retina.

Type 1 cannabinoid receptors (CB1Rs) are expressed in major retinal neurons within the rod-pathway suggesting a role in regulating night visual processing, but the underlying mechanisms remain poorly understood. Using acute rat retinal slices, we show that CB1R activation reduces glutamate release from rod bipolar cell (RBC) axon terminals onto AII and A17 amacrine cells through a pathway that requires exchange proteins directly activated by cAMP (EPAC1/2) signaling. Consequently, CB1R activation abrogates reciprocal GABAergic feedback inhibition from A17 amacrine cells. Moreover, the activation of CB1Rs in vivo enhances and prolongs the time course of the dim-light rod-driven visual responses, an effect that was eliminated when both GABAA and GABAC receptors were blocked. Altogether, our findings underscore a non-canonical mechanism by which cannabinoid signaling regulates RBC dyad synapses in the inner retina to regulate dim-light visual responses to fine-tune night vision.

Sodium salicylate improves detection of amplitude-modulated sound in mice.

Salicylate is commonly used to induce tinnitus in animals, but its underlying mechanism of action is still debated. We therefore tested its effects on the firing properties of neurons in the mouse inferior colliculus (IC). Salicylate induced a large decrease in the spontaneous activity and an increase of ∼20 dB SPL in the minimum threshold of single units. In response to sinusoidally modulated noise (SAM noise) single units showed both an increase in phase locking and improved rate coding. Mice also became better at detecting amplitude modulations, and a simple threshold model based on the IC population response could reproduce this improvement. The responses to dynamic random chords (DRCs) suggested that the improved AM encoding was due to a linearization of the cochlear output, resulting in larger contrasts during SAM noise. These effects of salicylate are not consistent with the presence of tinnitus, but should be taken into account when studying hyperacusis.

Bodily maps of uncertainty and surprise in musical chord progression and the underlying emotional response.

Music has profoundly shaped the human experience across cultures and generations, yet its impact on our minds and bodies remains elusive. This study examined how the perception of musical chord elicits bodily sensations and emotions through the brain's predictive processing. By deploying body-mapping tests and emotional evaluations on 527 participants exposed to chord progressions, we unveiled the intricate interplay between musical uncertainty, prediction error in eliciting specific bodily sensations and emotions. Our results demonstrated that certain chord progressions elicit cardiac and abdominal sensations, linked to interoception, and associated with aesthetic appreciation and positive valence. These findings highlight the crucial role of musical uncertainty and prediction error in emotional response and sound embodiment. This study offers insight into the potential connection between music-induced interoception and mental well-being, underscoring the musical effects on our minds and bodies.