Prithviraj Rajebhosale
Oct 23, 2024; 44:e0063242024-e0063242024
Cellular

Krista L. Hyde
Mar 11, 2009; 29:3019-3025
Development Plasticity Repair

Tessa E.S. Charlesworth
Sep 11, 2019; 39:7228-7243
Viewpoints

Nora D. Volkow
Dec 1, 2001; 21:9414-9418
Behavioral

Evdokia Menelaou
Aug 8, 2012; 32:10925-10939
BehavioralSystemsCognitive

Kyle E. Mathewson
Mar 4, 2009; 29:2725-2732
BehavioralSystemsCognitive

Yulia Lerner
Feb 23, 2011; 31:2906-2915
BehavioralSystemsCognitive

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRDs) are broad-impact multifactorial neurodegenerative diseases. Their complexity presents unique challenges for developing effective therapies. This review highlights research presented at the 2024 Society for Neuroscience meeting which emphasized the gut microbiome's role in AD pathogenesis by influencing brain function and neurodegeneration through the microbiota–gut–brain axis. This emerging evidence underscores the potential for targeting the gut microbiota to treat AD/ADRD.

Neural responses are naturally variable from one moment to the next, even when the stimulus is held constant. What factors might underlie this variability in neural population activity? We hypothesized that spontaneous fluctuations in cortical stimulus representations are created by changes in arousal state. We tested the hypothesis using a combination of fMRI, probabilistic decoding methods, and pupillometry. Human participants (20 female, 12 male) were presented with gratings of random orientation. Shortly after viewing the grating, participants reported its orientation and gave their level of confidence in this judgment. Using a probabilistic fMRI decoding technique, we quantified the precision of the stimulus representation in the visual cortex on a trial-by-trial basis. Pupil size was recorded and analyzed to index the observer's arousal state. We found that the precision of the cortical stimulus representation, reported confidence, and variability in the behavioral orientation judgments varied from trial to trial. Interestingly, these trial-by-trial changes in cortical and behavioral precision and confidence were linked to pupil size and its temporal rate of change. Specifically, when the cortical stimulus representation was more precise, the pupil dilated more strongly prior to stimulus onset and remained larger during stimulus presentation. Similarly, stronger pupil dilation during stimulus presentation was associated with higher levels of subjective confidence, a secondary measure of sensory precision, as well as improved behavioral performance. Taken together, our findings support the hypothesis that spontaneous fluctuations in arousal state modulate the fidelity of the stimulus representation in the human visual cortex, with clear consequences for behavior.

The GluN3A subunit of N-methyl-D-aspartate receptors (NMDARs) plays an established role in synapse development, but its contribution to neural circuits in the adult brain is less clear. Recent work has demonstrated that in select cell populations, GluN3A assembles with GluN1 to form GluN1/GluN3A receptors that are insensitive to glutamate and instead serve as functional excitatory glycine receptors (eGlyRs). Our understanding of these eGlyRs, and how they contribute to intrinsic excitability and synaptic communication within relevant networks of the developing and the mature brain, is only beginning to be uncovered. Here, using male and female mice, we demonstrate that GluN3A subunits are enriched in the adult ventral hippocampus (VH), where they localize to synaptic and extrasynaptic sites and can assemble as functional eGlyRs on CA1 pyramidal cells. GluN3A expression was barely detectable in the adult dorsal hippocampus (DH). We also observed a high GluN2B content in the adult VH, characterized by slow NMDAR current decay kinetics and a high sensitivity to the GluN2B-containing NMDAR antagonist ifenprodil. Interestingly, the GluN2B enrichment in the adult VH was dependent on GluN3A as GluN3A deletion accelerated NMDAR decay and reduced ifenprodil sensitivity in the VH, suggesting that GluN3A expression can regulate the balance of conventional NMDAR subunit composition at synaptic sites. Lastly, we found that GluN3A knock-out also enhanced both NMDAR-dependent calcium influx and NMDAR-dependent long-term potentiation in the VH. Together, these data reveal a novel role for GluN3A and eGlyRs in the control of ventral hippocampal circuits in the mature brain.

Injuries to the central nervous system (CNS) can cause severe neurological deficits. Axonal regrowth is a fundamental process for the reconstruction of compensatory neuronal networks after injury; however, it is extremely limited in the adult mammalian CNS. In this study, we conducted a loss-of-function genetic screen in cortical neurons, combined with a Web resource-based phenotypic screen, and identified synaptotagmin 4 (Syt4) as a novel regulator of axon elongation. Silencing Syt4 in primary cultured cortical neurons inhibits neurite elongation, with changes in gene expression involved in signaling pathways related to neuronal development. In a spinal cord injury model, inhibition of Syt4 expression in cortical neurons prevented axonal sprouting of the corticospinal tract, as well as neurological recovery after injury. These results provide a novel therapeutic approach to CNS injury by modulating Syt4 function.

Thalamocortical pathways from the rodent ventral posterior (VP) thalamic complex to the somatosensory cerebral cortex areas are a key model in modern neuroscience. However, beyond the intensively studied projection from medial VP (VPM) to the primary somatosensory area (S1), the wiring of these pathways remains poorly characterized. We combined micropopulation tract-tracing and single-cell transfection experiments to map the pathways arising from different portions of the VP complex in male mice. We found that pathways originating from different VP regions show differences in area/lamina arborization pattern and axonal varicosity size. Neurons from the rostral VPM subnucleus innervate trigeminal S1 in point-to-point fashion. In contrast, a caudal VPM subnucleus innervates heavily and topographically second somatosensory area (S2), but not S1. Neurons in a third, intermediate VPM subnucleus innervate through branched axons both S1 and S2, with markedly different laminar patterns in each area. A small anterodorsal subnucleus selectively innervates dysgranular S1. The parvicellular VPM subnucleus selectively targets the insular cortex and adjacent portions of S1 and S2. Neurons in the rostral part of the lateral VP nucleus (VPL) innervate spinal S1, while caudal VPL neurons simultaneously target S1 and S2. Rostral and caudal VP nuclei show complementary patterns of calcium-binding protein expression. In addition to the cortex, neurons in caudal VP subnuclei target the sensorimotor striatum. Our finding of a massive projection from VP to S2 separate from the VP projections to S1 adds critical anatomical evidence to the notion that different somatosensory submodalities are processed in parallel in S1 and S2.

Perivascular mural cells including vascular smooth cells (VSMCs) and pericytes are integral components of the vascular system. In the central nervous system (CNS), pericytes are also indispensable for the blood–brain barrier (BBB), blood–spinal cord barrier, and blood–retinal barrier and play key roles in maintaining cerebrovascular and neuronal functions. However, the functional specifications of pericytes between CNS and peripheral organs have not been resolved at the genetic and molecular levels. Hence, the generation of reliable CNS pericyte-specific models and genetic tools remains very challenging. Here, we report a new CNS pericyte marker in mice. This putative cation-transporting ATPase 13A5 (Atp13a5) marker was identified through single-cell transcriptomics, based on its specificity to brain pericytes. We further generated a knock-in model with both tdTomato reporter and Cre recombinase. Using this model to trace the distribution of Atp13a5-positive pericytes in mice, we found that the tdTomato reporter reliably labels the CNS pericytes, including the ones in spinal cord and retina but not peripheral organs. Interestingly, brain pericytes are likely shaped by the developing neural environment, as Atp13a5-positive pericytes start to appear around murine embryonic day 15 (E15) and expand along the cerebrovasculature. Thus, Atp13a5 is a specific marker of CNS pericyte lineage, and this Atp13a5-based model is a reliable tool to explore the heterogeneity of pericytes and BBB functions in health and diseases.

We used virus-mediated anterograde and retrograde tracing, optogenetic modulation, immunostaining, in situ hybridization, and patch-clamp recordings in acute brain slices to study the release mechanism and μ-opioid modulation of the dual glutamatergic/GABAergic inputs from the ventral tegmental area and supramammillary nucleus to the granule cells of the dorsal hippocampus of male and female mice. In keeping with previous reports showing that the two transmitters are released by separate active zones within the same terminals, we found that the short-term plasticity and pharmacological modulation of the glutamatergic and GABAergic currents are indistinguishable. We further found that glutamate and GABA release at these synapses are both virtually completely mediated by N- and P/Q-type calcium channels. We then investigated μ-opioid modulation of these synapses and found that activation of μ-opioid receptors (MORs) strongly inhibits the glutamate and GABA release, mostly through inhibition of presynaptic N-type channels. However, the modulation by MORs of these dual synapses is complex, as it likely includes also a disinhibition due to downmodulation of local GABAergic interneurons which make direct axo-axonic contacts with the dual glutamatergic/GABAergic terminals. We discuss how this opioid modulation may enhance LTP at the perforant path inputs, potentially contributing to reinforce memories of drug-associated contexts.

Large-scale genome-wide association studies (GWASs) have associated intronic variants in PDE4B, encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4b^M220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (10 tone–shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4b^M220T mice. At 24 h post-trauma, Pde4b^M220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4b^M220T mice also exhibited a slower decay in freezing at 15 and 30 d post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.

Neuregulin1 (Nrg1) signaling is critical for neuronal development and function from fate specification to synaptic plasticity. Type III Nrg1 is a synaptic protein which engages in bidirectional signaling with its receptor ErbB4. Forward signaling engages ErbB4 phosphorylation, whereas back signaling engages two known mechanisms: (1) local axonal PI3K-AKT signaling and (2) cleavage by -secretase resulting in cytosolic release of the intracellular domain (ICD), which can traffic to the nucleus (Bao et al., 2003; Hancock et al., 2008). To dissect the contribution of these alternate signaling strategies to neuronal development, we generated a transgenic mouse with a missense mutation (V₃₂₁L) in the Nrg1 transmembrane domain that disrupts nuclear back signaling with minimal effects on forward signaling or local back signaling and was previously found to be associated with psychosis (Walss-Bass et al., 2006). We combined RNA sequencing, retroviral fate mapping of neural stem cells, behavioral analyses, and various network analyses of transcriptomic data to investigate the effect of disrupting Nrg1 nuclear back signaling in the dentate gyrus (DG) of male and female mice. The V₃₂₁L mutation impairs nuclear translocation of the Nrg1 ICD and alters gene expression in the DG. V₃₂₁L mice show reduced stem cell proliferation, altered cell cycle dynamics, fate specification defects, and dendritic dysmorphogenesis. Orthologs of known schizophrenia (SCZ)-susceptibility genes were dysregulated in the V₃₂₁L DG. These genes coordinated a larger network with other dysregulated genes. Weighted gene correlation network analysis and protein interaction network analyses revealed striking similarity between DG transcriptomes of V₃₂₁L mouse and humans with SCZ.

Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel technique for noninvasive brain stimulation (NIBS). TUS delivered in a theta (5 Hz) burst pattern (tbTUS) induces plasticity in the human primary motor cortex (M1) for 30–60 min, showing promise for therapeutic development. Metaplasticity refers to activity-dependent changes in neural functions governing synaptic plasticity; depotentiation is the reversal of long-term potentiation (LTP) by a subsequent protocol with no effect alone. Metaplasticity can enhance plasticity induction and clinical efficacy of NIBS protocols. In our study, we compared four NIBS protocol combinations to investigate metaplasticity on tbTUS in humans of either sex. We delivered four interventions: (1) sham continuous theta burst stimulation with 150 pulses (cTBS150) followed by real tbTUS (tbTUS only), (2) real cTBS150 followed by sham tbTUS (cTBS only), (3) real cTBS150 followed by real tbTUS (metaplasticity), and (4) real tbTUS followed by real cTBS150 (depotentiation). We measured motor-evoked potential amplitude, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation (ICF), and short-interval intracortical facilitation before and up to 90 min after plasticity intervention. Plasticity effects lasted at least 60 min longer when tbTUS was primed with cTBS150 compared with tbTUS alone. Plasticity was abolished when cTBS150 was delivered after tbTUS. cTBS150 alone had no significant effect. No changes in M1 intracortical circuits were observed. Plasticity induction by tbTUS can be modified in manners consistent with homeostatic metaplasticity and depotentiation. This substantiates evidence that tbTUS induces LTP-like processes and suggests that metaplasticity can be harnessed in the therapeutic development of TUS.

The superior colliculus receives a direct projection from retinal ganglion cells. In primates, it remains unknown if the same ganglion cells also supply the lateral geniculate nucleus. To address this issue, a double-label experiment was performed in two male macaques. The animals fixated a target while injection sites were scouted in the superior colliculus by recording and stimulating with a tetrode. Once suitable sites were identified, cholera toxin subunit B-Alexa Fluor 488 was injected via an adjacent micropipette. In a subsequent acute experiment, cholera toxin subunit B-Alexa Fluor 555 was injected into the lateral geniculate nucleus at matching retinotopic locations. After a brief survival period, ganglion cells were examined in retinal flatmounts. The percentage of double-labeled cells varied locally, depending on the relative efficiency of retrograde transport by each tracer and the precision of retinotopic overlap of injection sites in each target nucleus. In counting boxes with extensive overlap, 76–98% of ganglion cells projecting to the superior colliculus were double labeled. Cells projecting to the superior colliculus constituted 4.0–6.7% of the labeled ganglion cell population. In one particularly large zone, there were 5,746 cells labeled only by CTB-AF555, 561cells double labeled by CTB-AF555 and CTB-AF488, but no cell labeled only by CTB-AF488. These data indicate that retinal input to the macaque superior colliculus arises from a collateral axonal branch supplied by ~5% of the ganglion cells that project to the lateral geniculate nucleus. Surprisingly, there exist no ganglion cells that project exclusively to the SC.

Harmonics are an integral part of music, speech, and vocalizations of animals. Since the rest of the auditory environment is primarily made up of nonharmonic sounds, the auditory system needs to perceptually separate the above two kinds of sounds. In mice, harmonics, generally with two-tone components (two-tone harmonic complexes, TTHCs), form an important component of vocal communication. Communication by pups during isolation from the mother and by adult males during courtship elicits typical behaviors in female mice—dams and adult courting females, respectively. Our study shows that the processing of TTHC is specialized in mice providing neural basis for perceptual differences between tones and TTHCs and also nonharmonic sounds. Investigation of responses in the primary auditory cortex (Au1) from in vivo extracellular recordings and two-photon Ca²⁺ imaging of excitatory and inhibitory neurons to TTHCs exhibit enhancement, suppression, or no-effect with respect to tones. Irrespective of neuron type, harmonic enhancement is maximized, and suppression is minimized when the fundamental frequencies (F₀) match the neuron's best fundamental frequency (BF₀). Sex-specific processing of TTHC is evident from differences in the distributions of neurons’ best frequency (BF) and best fundamental frequency (BF₀) in single units, differences in harmonic suppressed cases re-BF₀, independent of neuron types, and from pairwise noise correlations among excitatory and parvalbumin inhibitory interneurons. Furthermore, TTHCs elicit a higher response compared with two-tone nonharmonics in females, but not in males. Thus, our study shows specialized neural processing of TTHCs over tones and nonharmonics, highlighting local network specialization among different neuronal types.

Key event-related potentials (ERPs) of perceptual decision-making such as centroparietal positivity (CPP) elucidate how evidence is accumulated toward a given choice. Furthermore, this accumulation can be impacted by visual target selection signals such as the N2 contralateral (N2c). How these underlying neural mechanisms of perceptual decision-making are influenced by the spatial congruence of distractors relative to target stimuli remains unclear. Here, we used electroencephalography (EEG) in humans of both sexes to investigate the effect of distractor spatial congruency (same vs different hemifield relative to targets) on perceptual decision-making. We confirmed that responses for perceptual decisions were slower for spatially incongruent versus congruent distractors of high salience. Similarly, markers of target selection (N2c peak amplitude) and evidence accumulation (CPP slope) were found to be lower when distractors were spatially incongruent versus congruent. To evaluate the effects of congruency further, we applied drift diffusion modeling to participant responses, which showed that larger amplitudes of both ERPs were correlated with shorter nondecision times when considering the effect of congruency. The modeling also suggested that congruency's effect on behavior occurred prior to and during evidence accumulation when considering the effects of the N2c peak and CPP slope. These findings point to spatially incongruent distractors, relative to congruent distractors, influencing decisions as early as the initial sensory processing phase and then continuing to exert an effect as evidence is accumulated throughout the decision-making process. Overall, our findings highlight how key electrophysiological signals of perceptual decision-making are influenced by the spatial congruence of target and distractor.

Plasticity in the subcortical motor basal ganglia–thalamo–cerebellar network plays a key role in the acquisition and control of long-term memory for new procedural skills, from the formation of population trajectories controlling trained motor skills in the striatum to the adaptation of sensorimotor maps in the cerebellum. However, recent findings demonstrate the involvement of a wider cortical and subcortical brain network in the consolidation and control of well-trained actions, including a brain region traditionally associated with declarative memory—the hippocampus. Here, we probe which role these subcortical areas play in skilled motor sequence control, from sequence feature selection during planning to their integration during sequence execution. An fMRI dataset (N = 24; 14 females) collected after participants learnt to produce four finger press sequences entirely from memory with high movement and timing accuracy over several days was examined for both changes in BOLD activity and their informational content in subcortical regions of interest. Although there was a widespread activity increase in effector-related striatal, thalamic, and cerebellar regions, in particular during sequence execution, the associated activity did not contain information on the motor sequence identity. In contrast, hippocampal activity increased during planning and predicted the order of the upcoming sequence of movements. Our findings suggest that the hippocampus preorders movements for skilled action sequences, thus contributing to the higher-order control of skilled movements that require flexible retrieval. These findings challenge the traditional taxonomy of episodic and procedural memory and carry implications for the rehabilitation of individuals with neurodegenerative disorders.

The precise regulation of Ca²⁺ signals plays a crucial role in the physiological functions of neurons. Here, we investigated the rapid effect of glucocorticoids on Ca²⁺ signals in cultured hippocampal neurons from both female and male rats. In cultured hippocampal neurons, glucocorticoids inhibited the spontaneous somatic Ca²⁺ spikes generated by Kv2.1-organized Ca²⁺ microdomains. Furthermore, glucocorticoids rapidly reduced the cell surface expressions of Kv2.1 and Ca_V1.2 channels in hippocampal neurons. In HEK293 cells transfected with Kv2.1 alone, glucocorticoids significantly reduced the surface expression of Kv2.1 with little effect on K⁺ currents. In HEK293 cells transfected with Ca_V1.2 alone, glucocorticoids inhibited Ca_V1.2 currents but had no effect on the cell surface expression of Ca_V1.2. Notably, in the presence of wild-type Kv2.1, glucocorticoids caused a decrease in the surface expression of Ca_V1.2 channels in HEK293 cells. However, this effect was not observed in the presence of nonclustering Kv2.1S586A mutant channels. Live-cell imaging showed that glucocorticoids rapidly decreased Kv2.1 clusters on the plasma membrane. Correspondingly, Western blot results indicated a significant increase in the cytoplasmic level of Kv2.1, suggesting the endocytosis of Kv2.1 clusters. Glucocorticoids rapidly decreased the intracellular cAMP concentration and the phosphorylation level of PKA in hippocampal neurons. The PKA inhibitor H89 mimicked the effect of glucocorticoids on Kv2.1, while the PKA agonist forskolin abrogated the effect. In conclusion, glucocorticoids rapidly suppress Ca_V1.2-mediated Ca²⁺ signals in hippocampal neurons by promoting the endocytosis of Kv2.1 channel clusters through reducing PKA activity.

Seven guest collaborators bring new eyes to a Smithsonian museum founder’s collection of American art

The work of Diné artist DY Begay, now on view at the National Museum of the American Indian, blends tradition and modernity

The Smithsonian Design Triennial presents 25 commissions that explore the physical and conceptual ideas of shelter and refuge

A Smithsonian curator reflects back on the artistic legend, a "Renaissance man" with 28 Grammys to his name, who died Sunday at 91 years old

Policy makers should support a broad array of approaches to overhauling global food systems, [...]

Milan - European governments must help combat [...]

Rome - Governments ought to review the [...]

The Joint Meeting of the Finance and Programme Committees met yesterday morning. In [...]

5 December 2014, Rome – At the closure of the FAO Council held today, the [...]

Last Friday the Council closed its week-long session with a standing ovation having reached consensus on the Programme of Work and Budget. In the past, budget negotiations have extended well [...]

New York- FAO Director-General José Graziano da Silva and the President of the UN Security Council (UNSC), Ambassador Ismael Gaspar Martins, have concurred upon the importance of using FAO’s regular [...]

The FMM is a funding mechanism for partners willing to contribute unearmarked funds or slightly earmarked funds. Created in 2010, the FMM is currently supported by the Kingdoms of Belgium, [...]

Since the 1990s, rural transformations have helped millions of people exit poverty while remaining in rural areas. This underscores an important fact: revitalising rural economies helps create jobs for rural [...]

Addressing the plenary meeting in the closing session of the 159^th Session of the Council, the Director-General expressed his appreciation to delegates for their commitment and hard work to [...]

On Friday, 7 December during the 160th session of the Council, a side event on the Africa Solidarity Trust [...]

The Food and Agriculture Organization of the United Nations, through the Globally Important Agricultural Heritage Systems (GIAHS) Programme, will organise the International Symposium on Globally Important Agricultural Heritage Systems and Family Farming from [...]

The Food and Agriculture Organization of the United Nations (FAO), through the Globally Important Agricultural Heritage Systems (GIAHS) Programme, is organizing the International Conference on Globally Important Agricultural Heritage Systems 2021 [...]

Rome – The Food and Agriculture Organization of the United Nations (FAO), on behalf of the International Plant Protection Convention (IPPC) has joined forces with the Comité de [...]

The World Pulses Day Secretariat welcomes your participation in an open event to celebrate World Pulses Day 2022 Thursday, 10 February [...]