Miracle-dz/UniFAR-FTUs huggingface dataset:
Visual Sampling Predicts Hippocampal Activity

Eye movements serve to accumulate information from the visual world, contributing to the formation of coherent memory representations that support cognition and behavior. The hippocampus and the oculomotor network are well connected anatomically through an extensive set of polysynaptic pathways. However, the extent to which visual sampling behavior is related to functional responses in the hippocampus during encoding has not been studied directly in human neuroimaging. In the current study, participants engaged in a face processing task while brain responses were recorded with fMRI and eye movements were monitored simultaneously. The number of gaze fixations that a participant made on a given trial was correlated significantly with hippocampal activation such that more fixations were associated with stronger hippocampal activation. Similar results were also found in the fusiform face area, a face-selective perceptual processing region. Notably, the number of fixations was associated with stronger hippocampal activation when the presented faces were novel, but not when the faces were repeated. Increases in fixations during viewing of novel faces also led to larger repetition-related suppression in the hippocampus, indicating that this fixation–hippocampal relationship may reflect the ongoing development of lasting representations. Together, these results provide novel empirical support for the idea that visual exploration and hippocampal binding processes are inherently linked. SIGNIFICANCE STATEMENT The hippocampal and oculomotor networks have each been studied extensively for their roles in the binding of information and gaze function, respectively. Despite the evidence that individuals with amnesia whose damage includes the hippocampus show alterations in their eye movement patterns and recent findings that the two systems are anatomically connected, it has not been demonstrated whether visual exploration is related to hippocampal activity in neurologically intact adults. In this combined fMRI–eye-tracking study, we show how hippocampal responses scale with the number of gaze fixations made during viewing of novel, but not repeated, faces. These findings provide new evidence suggesting that the hippocampus plays an important role in the binding of information, as sampled by gaze fixations, during visual exploration.
Relief of Mg2+-Dependent Inhibition of TRPM1 by PKCα at the Rod Bipolar Cell Synapse

In the retina, light onset hyperpolarizes photoreceptors and depolarizes ON bipolar cells at the sign inverting photoreceptor–ON bipolar cell synapse. Transmission at this synapse is mediated by a signaling cascade comprised of mGluR6, a G-protein containing Gαo, and the cation channel TRP melastatin 1 (TRPM1). This system is thought to be common to both the rod- and ON-cone-driven pathways, which control vision under scotopic and photopic conditions, respectively. In this study, we present evidence that the rod pathway is uniquely susceptible to modulation by PKCα at the rod–rod bipolar cell synapse. Decreased production of DAG (an activator of PKC) by inhibition of PIP2 (phosphatidylinositol-4,5-bisphosphate) hydrolysis caused depression of the TRPM1 current. Conversely, addition of a DAG analog, 2-acetyl-1-oleoyl-sn-glycerol (OAG), potentiated the current in rod bipolar cells but not in ON-cone bipolar cells. The potentiating effects of OAG were absent both in mutant mice that lack PKCα expression and in wild-type mice in which enzymatic activity of PKCα was pharmacologically inhibited. In addition, we found that, like other members of the TRPM subfamily, TRPM1 current is susceptible to voltage-independent inhibition by intracellular magnesium, and that modulation by PKCα relieves this inhibition, as the potentiating effects of OAG are absent in low intracellular magnesium. We conclude that activation of PKCα initiates a modulatory mechanism at the rod–rod bipolar cell synapse whose function is to reduce inhibition of the TRPM1 current by magnesium, thereby increasing the gain of transmission at this synapse.
Regionalized Loss of Parvalbumin Interneurons in the Cerebral Cortex of Mice with Deficits in GFRα1 Signaling

Inhibitory interneurons are crucially important for cerebral cortex function and behavior. The mechanisms controlling inhibitory interneuron diversification and allocation to distinct cortical areas remain poorly understood. GDNF (glial cell line-derived neurotrophic factor) and its receptor GFRα1 have been implicated in the development of GABAergic precursors but, because of the early lethality of null mutants, their roles in postnatal maturation and function of cortical interneurons are unknown. “cis-only” mutant mice lack GFRα1 only in cells that do not express the RET signaling receptor subunit and survive to adulthood. At birth, both null mutants and cis-only mice showed a specific loss of GABAergic interneurons in rostro- and caudolateral cortical regions but not in more medial areas. Unexpectedly, the adult cortex of cis-only mice displayed a complete loss of parvalbumin (PV)-expressing GABAergic interneurons in discrete regions (PV holes) interspersed among areas of normal PV cell density. PV holes predominantly occurred in the visual and frontal cortices, and their size could be affected by neuronal activity. Consistent with deficits in cortical inhibitory activity, these mice showed enhanced cortical excitability, increased sensitivity to epileptic seizure, and increased social behavior. We propose that GFRα1 signaling guides the development of a subset of PV-expressing GABAergic interneurons populating discrete regions of the cerebral cortex and may thus contribute to the diversification and allocation of specific cortical interneuron subtypes.
Garlic attenuates histological and histochemical alterations in livers of Schistosoma mansoni infected mice

Interest in screening for new anti-schistosomal agents is growing because of increased concerns about resistance to and safety of praziquantel. We investigated the anti-schistosomal action of prophylactic and therapeutic doses of garlic on the histological and histochemical alterations caused by Schistosoma mansoni infection. Livers of infected mice were characterized by granulomas, periportal inflammation and fibrosis, hepatocyte vacuolation, fatty degeneration and necrosis, and hypertrophy and pigmentation of Kupffer cells. Significant depletion of carbohydrates and increased lipid vacuoles also were observed. All garlic regimens caused suppression of granuloma formation and amelioration of histological and histochemical changes; the continuous treatment protocol produced the best results. Garlic appears to be a safe and economical anti-schistosomal adjuvant for attenuating the pathogenicity of schistosomiasis.
Ventral Tegmental Afferents in Stress-Induced Reinstatement: The Role of cAMP Response Element-Binding Protein

The transcription factor cAMP response element-binding protein (CREB) is required for stress- but not drug-induced reinstatement of cocaine conditioned place preference. To reveal the neural circuitry associated with this CREB dependence, we injected a retrograde tracer into the ventral tegmental area (VTA) and identified afferents that were activated after stress or cocaine exposure in both naive and cocaine-conditioned mice. Neuronal activation, as assessed by Fos expression, was greatly reduced in the dorsal and ventral bed nucleus of the stria terminalis (BNST), lateral septum, and nucleus accumbens shell in mice lacking CREB (CREBαΔ mice) after a 6 min swim stress but not after cocaine exposure (20 mg/kg). Additionally, activation of VTA afferent neurons in the ventral BNST and the infralimbic cortex in CREBαΔ mice was blunted in response to stress. This pattern of neuronal activation persisted in mice that were conditioned to a cocaine place preference procedure before stress exposure. Furthermore, lidocaine inactivation (0.4 μl, 4%) studies demonstrated the necessity of BNST activation for swim-stress-induced reinstatement of cocaine-conditioned reward. Together, the present studies demonstrate that CREB is required for the activation of a unique circuit that converges on the dopamine reward pathway to elicit reinstatement of drug reward and points to the BNST as a key intersection between stress and reward circuits.
Local Circuits of V1 Layer 4B Neurons Projecting to V2 Thick Stripes Define Distinct Cell Classes and Avoid Cytochrome Oxidase Blobs

Decades of anatomical studies on the primate primary visual cortex (V1) have led to a detailed diagram of V1 intrinsic circuitry, but this diagram lacks information about the output targets of V1 cells. Understanding how V1 local processing relates to downstream processing requires identification of neuronal populations defined by their output targets. In primates, V1 layers (L)2/3 and 4B send segregated projections to distinct cytochrome oxidase (CO) stripes in area V2: neurons in CO blob columns project to thin stripes while neurons outside blob columns project to thick and pale stripes, suggesting functional specialization of V1-to-V2 CO streams. However, the conventional diagram of V1 shows all L4B neurons, regardless of their soma location in blob or interblob columns, as projecting selectively to CO blobs in L2/3, suggesting convergence of blob/interblob information in L2/3 blobs and, possibly, some V2 stripes. However, it is unclear whether all L4B projection neurons show similar local circuitries. Using viral-mediated circuit tracing, we have identified the local circuits of L4B neurons projecting to V2 thick stripes in macaque. Consistent with previous studies, we found the somata of this L4B subpopulation to reside predominantly outside blob columns; however, unlike previous descriptions of local L4B circuits, these cells consistently projected outside CO blob columns in all layers. Thus, the local circuits of these L4B output neurons, just like their extrinsic projections to V2, preserve CO streams. Moreover, the intra-V1 laminar patterns of axonal projections identify two distinct neuron classes within this L4B subpopulation, including a rare novel neuron type, suggestive of two functionally specialized output channels. SIGNIFICANCE STATEMENT Conventional diagrams of primate primary visual cortex (V1) depict neuronal connections within and between different V1 layers, but lack information about the cells' downstream targets. This information is critical to understanding how local processing in V1 relates to downstream processing. We have identified the local circuits of a population of cells in V1 layer (L)4B that project to area V2. These cells' local circuits differ from classical descriptions of L4B circuits in both the laminar and functional compartments targeted by their axons, and identify two neuron classes. Our results demonstrate that both local intra-V1 and extrinsic V1-to-V2 connections of L4B neurons preserve CO-stream segregation, suggesting that across-stream integration occurs downstream of V1, and that output targets dictate local V1 circuitry.
The Protein Tyrosine Phosphatase Shp2 Regulates Oligodendrocyte Differentiation and Early Myelination and Contributes to Timely Remyelination

Shp2 is a nonreceptor protein tyrosine phosphatase that has been shown to influence neurogenesis, oligodendrogenesis, and oligodendrocyte differentiation. Furthermore, Shp2 is a known regulator of the Akt/mammalian target of rapamycin and ERK signaling pathways in multiple cellular contexts, including oligodendrocytes. Its role during later postnatal CNS development or in response to demyelination injury has not been examined. Based on the current studies, we hypothesize that Shp2 is a negative regulator of CNS myelination. Using transgenic mouse technology, we show that Shp2 is involved in oligodendrocyte differentiation and early myelination, but is not necessary for myelin maintenance. We also show that Shp2 regulates the timely differentiation of oligodendrocytes following lysolecithin-induced demyelination, although apparently normal remyelination occurs at a delayed time point. These data suggest that Shp2 is a relevant therapeutic target in demyelinating diseases such as multiple sclerosis. SIGNIFICANCE STATEMENT In the present study, we show that the protein phosphatase Shp2 is an important mediator of oligodendrocyte differentiation and myelination, both during developmental myelination as well as during myelin regeneration. We provide important insight into the signaling mechanisms regulating myelination and propose that Shp2 acts as a transient brake to the developmental myelination process. Furthermore, we show that Shp2 regulates oligodendrocyte differentiation following demyelination and therefore has important therapeutic implications in diseases such as multiple sclerosis.
Recruitment of Additional Corticospinal Pathways in the Human Brain with State-Dependent Paired Associative Stimulation

Standard brain stimulation protocols modify human motor cortex excitability by modulating the gain of the activated corticospinal pathways. However, the restoration of motor function following lesions of the corticospinal tract requires also the recruitment of additional neurons to increase the net corticospinal output. For this purpose, we investigated a novel protocol based on brain state-dependent paired associative stimulation. Motor imagery (MI)-related electroencephalography was recorded in healthy males and females for brain state-dependent control of both cortical and peripheral stimulation in a brain–machine interface environment. State-dependency was investigated with concurrent, delayed, and independent stimulation relative to the MI task. Specifically, sensorimotor event-related desynchronization (ERD) in the β-band (16–22 Hz) triggered peripheral stimulation through passive hand opening by a robotic orthosis and transcranial magnetic stimulation to the respective cortical motor representation, either synchronously or subsequently. These MI-related paradigms were compared with paired cortical and peripheral input applied independent of the brain state. Cortical stimulation resulted in a significant increase in corticospinal excitability only when applied brain state-dependently and synchronously to peripheral input. These gains were resistant to a depotentiation task, revealed a nonlinear evolution of plasticity, and were mediated via the recruitment of additional corticospinal neurons rather than via synchronization of neuronal firing. Recruitment of additional corticospinal pathways may be achieved when cortical and peripheral inputs are applied concurrently, and during β-ERD. These findings resemble a gating mechanism and are potentially important for developing closed-loop brain stimulation for the treatment of hand paralysis following lesions of the corticospinal tract. SIGNIFICANCE STATEMENT The activity state of the motor system influences the excitability of corticospinal pathways to external input. State-dependent interventions harness this property to increase the connectivity between motor cortex and muscles. These stimulation protocols modulate the gain of the activated pathways, but not the overall corticospinal recruitment. In this study, a brain–machine interface paired peripheral stimulation through passive hand opening with transcranial magnetic stimulation to the respective cortical motor representation during volitional β-band desynchronization. Cortical stimulation resulted in the recruitment of additional corticospinal pathways, but only when applied brain state-dependently and synchronously to peripheral input. These effects resemble a gating mechanism and may be important for the restoration of motor function following lesions of the corticospinal tract.
Rho GTPase

Ras GTPases and phosphatidylinositol 3-kinases mediate intracellular signaling in directed cell migration. During chemotaxis, cells spatially control the activation of Ras/PI (3,4,5)-trisphosphate (PIP3) signaling and translate extracellular chemical gradients into intracellular signal cascades. This process is called directional sensing, and enables persistent cell migration with extraordinary sensitivity in shallow, unstable gradients of chemoattractants. In our recent study, we identified a Rho GTPase and its guanine nucleotide exchange factor (GEF) as molecular modulators that transmit signals from G protein-coupled receptors to Ras/PIP3 signaling pathways. The proteins spatially stabilize Ras activation and PIP3 production toward higher concentrations of chemoattractants. Unlike known roles of Rho GTPases and GEFs, the function of these proteins in directional sensing is independent of the actin cytoskeleton and cell morphology. Our findings provide novel mechanistic insight into the precision of directional cell migration.
The effective therapy of cyclosporine A with drug delivery system in experimental colitis

Cyclosporine A (CyA) is a useful immunosuppressive agent for steroid-dependent or steroid-refractory ulcerative colitis. However, side effects have been reported in clinical trials of ulcerative colitis treated with CyA. Biodegradable microspheres (MS) have been investigated as drug delivery system. We evaluated the effect of a drug delivery system with poly(d,l-lactic acid)-MS containing CyA. Colitis was induced in C57BL/6 mice by 3% dextran sulfate sodium (DSS). Mice with DSS-induced colitis were treated with oral administration of CyA or CyA-MS: CyA (0.2 mg/kg/day)-MS; CyA (2 mg/kg/kg)-MS). Serum levels of CyA were significantly less elevated after oral administration of CyA (2 mg/kg/day)-MS compared with CyA (2 mg/kg/day) (CyA (2 mg/kg/day), 44.7 ± 0.8 ng/ml; CyA (2 mg/kg/day)-MS, 7.7 ± 1.3 ng/ml). The body weight at day 10 was significantly recovered in the mice treated with CyA (0.2 mg/kg/day)-MS and CyA (2 mg/kg/day)-MS compared with CyA (0). The histological score and myeloperoxidase activity in the mice treated with CyA-MS was significantly lower than CyA (0). Gene expressions of interleukin-1β (IL-1β), IL-6, and CXCL1 in the mice treated with CyA (0.2 mg/kg/day)-MS and CyA (2 mg/kg/day)-MS were downregulated compared with CyA (0)-MS. CyA-MS might be possible to treat ulcerative colitis effectively by decreasing the total dosage without the elevation of the serum level or the side effects of CyA.
Mouth and Voice: A Relationship between Visual and Auditory Preference in the Human Superior Temporal Sulcus

Cortex in and around the human posterior superior temporal sulcus (pSTS) is known to be critical for speech perception. The pSTS responds to both the visual modality (especially biological motion) and the auditory modality (especially human voices). Using fMRI in single subjects with no spatial smoothing, we show that visual and auditory selectivity are linked. Regions of the pSTS were identified that preferred visually presented moving mouths (presented in isolation or as part of a whole face) or moving eyes. Mouth-preferring regions responded strongly to voices and showed a significant preference for vocal compared with nonvocal sounds. In contrast, eye-preferring regions did not respond to either vocal or nonvocal sounds. The converse was also true: regions of the pSTS that showed a significant response to speech or preferred vocal to nonvocal sounds responded more strongly to visually presented mouths than eyes. These findings can be explained by environmental statistics. In natural environments, humans see visual mouth movements at the same time as they hear voices, while there is no auditory accompaniment to visual eye movements. The strength of a voxel's preference for visual mouth movements was strongly correlated with the magnitude of its auditory speech response and its preference for vocal sounds, suggesting that visual and auditory speech features are coded together in small populations of neurons within the pSTS. SIGNIFICANCE STATEMENT Humans interacting face to face make use of auditory cues from the talker's voice and visual cues from the talker's mouth to understand speech. The human posterior superior temporal sulcus (pSTS), a brain region known to be important for speech perception, is complex, with some regions responding to specific visual stimuli and others to specific auditory stimuli. Using BOLD fMRI, we show that the natural statistics of human speech, in which voices co-occur with mouth movements, are reflected in the neural architecture of the pSTS. Different pSTS regions prefer visually presented faces containing either a moving mouth or moving eyes, but only mouth-preferring regions respond strongly to voices.
Spike and Neuropeptide-Dependent Mechanisms Control GnRH Neuron Nerve Terminal Ca2+ over Diverse Time Scales

Fast cell-to-cell communication in the brain is achieved by action potential-dependent synaptic release of neurotransmitters. The fast kinetics of transmitter release are determined by transient Ca2+ elevations in presynaptic nerve terminals. Neuromodulators have previously been shown to regulate transmitter release by inhibiting presynaptic Ca2+ influx. Few studies to date have demonstrated the opposite, that is, neuromodulators directly driving presynaptic Ca2+ rises and increases in nerve terminal excitability. Here we use GCaMP Ca2+ imaging in brain slices from mice to address how nerve terminal Ca2+ is controlled in gonadotropin-releasing hormone (GnRH) neurons via action potentials and neuromodulators. Single spikes and bursts of action potentials evoked fast, voltage-gated Ca2+ channel-dependent Ca2+ elevations. In contrast, brief exposure to the neuropeptide kisspeptin-evoked long-lasting Ca2+ plateaus that persisted for tens of minutes. Neuropeptide-mediated Ca2+ elevations were independent of action potentials, requiring Ca2+ entry via voltage-gated Ca2+ channels and transient receptor potential channels in addition to release from intracellular store mechanisms. Together, these data reveal that neuromodulators can exert powerful and long-lasting regulation of nerve terminal Ca2+ independently from actions at the soma. Thus, GnRH nerve terminal function is controlled over disparate timescales via both classical spike-dependent and nonclassical neuropeptide-dependent mechanisms. SIGNIFICANCE STATEMENT Nerve terminals are highly specialized regions of a neuron where neurotransmitters and neurohormones are released. Many neuroendocrine neurons release neurohormones in long-duration bursts of secretion. To understand how this is achieved, we have performed live Ca2+ imaging in the nerve terminals of gonadotropin-releasing hormone neurons. We find that bursts of action potentials and local neuropeptide signals are both capable of evoking large increases in nerve terminal Ca2+. Increases in Ca2+ driven by spike bursts last seconds; however, the increases in nerve terminal Ca2+ driven by neuropeptides can persist for tens of minutes. These findings reveal new mechanisms by which neuroendocrine nerve terminal Ca2+ can be controlled in the brain.
Gating of Sensory Input by Spontaneous Cortical Activity

The activity of neural populations is determined not only by sensory inputs but also by internally generated patterns. During quiet wakefulness, the brain produces spontaneous firing events that can spread over large areas of cortex and have been suggested to underlie processes such as memory recall and consolidation. Here we demonstrate a different role for spontaneous activity in sensory cortex: gating of sensory inputs. We show that population activity in rat auditory cortex is composed of transient 50–100 ms packets of spiking activity that occur irregularly during silence and sustained tone stimuli, but reliably at tone onset. Population activity within these packets had broadly consistent spatiotemporal structure, but the rate and also precise relative timing of action potentials varied between stimuli. Packet frequency varied with cortical state, with desynchronized state activity consistent with superposition of multiple overlapping packets. We suggest that such packets reflect the sporadic opening of a “gate” that allows auditory cortex to broadcast a representation of external sounds to other brain regions.