Phase precession in the human hippocampus and entorhinal cortex.

Knowing where we are, where we have been, and where we are going is critical to many behaviors, including navigation and memory. One potential neuronal mechanism underlying this ability is phase precession, in which spatially tuned neurons represent sequences of positions by activating at progressively earlier phases of local network theta oscillations. Based on studies in rodents, researchers have hypothesized that phase precession may be a general neural pattern for representing sequential events for learning and memory. By recording human single-neuron activity during spatial navigation, we show that spatially tuned neurons in the human hippocampus and entorhinal cortex exhibit phase precession. Furthermore, beyond the neural representation of locations, we show evidence for phase precession related to specific goal states. Our findings thus extend theta phase precession to humans and suggest that this phenomenon has a broad functional role for the neural representation of both spatial and non-spatial information.

Representational geometry of perceptual decisions in the monkey parietal cortex.

Lateral intraparietal (LIP) neurons represent formation of perceptual decisions involving eye movements. In circuit models for these decisions, neural ensembles that encode actions compete to form decisions. Consequently, representation and readout of the decision variables (DVs) are implemented similarly for decisions with identical competing actions, irrespective of input and task context differences. Further, DVs are encoded as partially potentiated action plans through balance of activity of action-selective ensembles. Here, we test those core principles. We show that in a novel face-discrimination task, LIP firing rates decrease with supporting evidence, contrary to conventional motion-discrimination tasks. These opposite response patterns arise from similar mechanisms in which decisions form along curved population-response manifolds misaligned with action representations. These manifolds rotate in state space based on context, indicating distinct optimal readouts for different tasks. We show similar manifolds in lateral and medial prefrontal cortices, suggesting similar representational geometry across decision-making circuits.

Correlated Neural Activity across the Brains of Socially Interacting Bats.

Social interactions occur between multiple individuals, but what is the detailed relationship between the neural dynamics across their brains? To address this question across timescales and levels of neural activity, we used wireless electrophysiology to simultaneously record from pairs of bats engaged in a wide range of natural social interactions. We found that neural activity was remarkably correlated between their brains over timescales from seconds to hours. The correlation depended on a shared social environment and was most prominent in high frequency local field potentials (>30 Hz), followed by local spiking activity. Furthermore, the degree of neural correlation covaried with the extent of social interactions, and an increase in correlation preceded their initiation. These results show that inter-brain correlation is an inherent feature of natural social interactions, reveal the domain of neural activity where it is most prominent, and provide a foundation for studying its functional role in social behaviors.

Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems.

The dorsal raphe (DR) constitutes a major serotonergic input to the forebrain and modulates diverse functions and brain states, including mood, anxiety, and sensory and motor functions. Most functional studies to date have treated DR serotonin neurons as a single population. Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell-body distributions within the DR and differentially co-express a vesicular glutamate transporter. Further, amygdala- and frontal-cortex-projecting DR serotonin neurons have largely complementary whole-brain collateralization patterns, receive biased inputs from presynaptic partners, and exhibit opposite responses to aversive stimuli. Gain- and loss-of-function experiments suggest that amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal-cortex-projecting neurons promote active coping in the face of challenge. These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.

Transcranial magnetic stimulation to frontal but not occipital cortex disrupts endogenous attention.

Covert endogenous (voluntary) attention improves visual performance. Human neuroimaging studies suggest that the putative human homolog of macaque frontal eye fields (FEF+) is critical for this improvement, whereas early visual areas are not. Yet, correlational MRI methods do not manipulate brain function. We investigated whether rFEF+ or V1/V2 plays a causal role in endogenous attention. We used transcranial magnetic stimulation (TMS) to alter activity in the visual cortex or rFEF+ when observers performed an orientation discrimination task while attention was manipulated. On every trial, they received double-pulse TMS at a predetermined site (stimulated region) around V1/V2 or rFEF+. Two cortically magnified gratings were presented, one in the stimulated region (contralateral to the stimulated area) and another in the symmetric (ipsilateral) nonstimulated region. Grating contrast was varied to measure contrast response functions (CRFs) for all attention and stimulation combinations. In experiment 1, the CRFs were similar at the stimulated and nonstimulated regions, indicating that early visual areas do not modulate endogenous attention during stimulus presentation. In contrast, occipital TMS eliminates exogenous (involuntary) attention effects on performance [A. Fernández, M. Carrasco,Curr. Biol. 30, 4078-4084 (2020)]. In experiment 2, rFEF+ stimulation decreased the overall attentional effect; neither benefits at the attended location nor costs at the unattended location were significant. The frequency and directionality of microsaccades mimicked this pattern: Whereas occipital stimulation did not affect microsaccades, rFEF+ stimulation caused a higher microsaccade rate directed toward the stimulated hemifield. These results provide causal evidence of the role of this frontal region for endogenous attention.

Symmetry in Frontal But Not Motor and Somatosensory Cortical Projections.

The neocortex and striatum are topographically organized for sensory and motor functions. While sensory and motor areas are lateralized for touch and motor control, respectively, frontal areas are involved in decision-making, where lateralization of function may be less important. This study contrasted the topographic precision of cell-type-specific ipsilateral and contralateral cortical projections while varying the injection site location in transgenic mice of both sexes. While sensory cortical areas had strongly topographic outputs to the ipsilateral cortex and striatum, they were weaker and not as topographically precise to contralateral targets. The motor cortex had somewhat stronger projections but still relatively weak contralateral topography. In contrast, frontal cortical areas had high degrees of topographic similarity for both ipsilateral and contralateral projections to the cortex and striatum. Corticothalamic organization is mainly ipsilateral, with weaker, more medial contralateral projections. Corticostriatal computations might integrate input outside closed basal ganglia loops using contralateral projections, enabling the two hemispheres to act as a unit to converge on one result in motor planning and decision-making.

Dissociable Representations of Decision Variables within Subdivisions of the Macaque Orbital and Ventrolateral Frontal Cortex.

The ventral frontal cortex (VFC) in macaques is involved in many affective and cognitive processes and has a key role in flexibly guiding reward-based decision-making. VFC is composed of a set of anatomically distinct subdivisions that are within the orbitofrontal cortex, ventrolateral prefrontal cortex, and anterior insula. In part, because prior studies have lacked the resolution to test for differences, it is unclear if neural representations related to decision-making are dissociable across these subdivisions. Here we recorded the activity of thousands of neurons within eight anatomically defined subdivisions of VFC in male macaque monkeys performing a two-choice probabilistic task for different fruit juice outcomes. We found substantial variation in the encoding of decision variables across these eight subdivisions. Notably, ventrolateral Area 12l was unique relative to the other areas that we recorded from as the activity of single neurons integrated multiple attributes when monkeys evaluated the different choice options. Activity within Area 12o, in contrast, more closely represented reward probability and whether reward was received on a given trial. Orbitofrontal Area 11m/l contained more specific representations of the quality of the outcome that could be earned later on. We also found that reward delivery encoding was highly distributed across all VFC subdivisions, while the properties of the reward, such as its flavor, were more strongly represented in Areas 11m/l and 13m. Taken together, our work reveals the diversity of encoding within the various anatomically distinct subdivisions of VFC in primates.

Neural Representations of Post-Decision Accuracy and Reward Expectation in the Caudate Nucleus and Frontal Eye Field.

Performance monitoring that supports ongoing behavioral adjustments is often examined in the context of either choice confidence for perceptual decisions (i.e., "did I get it right?") or reward expectation for reward-based decisions (i.e., "what reward will I receive?"). However, our understanding of how the brain encodes these distinct evaluative signals remains limited because they are easily conflated, particularly in commonly used two-alternative tasks with symmetric rewards for correct choices. Previously we used a motion-discrimination task with asymmetric rewards to identify neural substrates of forming reward-biased perceptual decisions in the caudate nucleus (part of the striatum in the basal ganglia) and the frontal eye field (FEF, in prefrontal cortex). Here we leveraged this task design to partially decouple estimates of accuracy and reward expectation and examine their impacts on subsequent decisions and their representations in those two brain areas. We identified distinguishable representations of these two evaluative signals in individual caudate and FEF neurons, with regional differences in their distribution patterns and time courses. We observed that well-trained monkeys (both sexes) used both evaluative signals, infrequently but consistently, to adjust their subsequent decisions. We found further that these behavioral adjustments had reliable relationships with the neural representations of both evaluative signals in caudate, but not FEF. These results suggest that the cortico-striatal decision network may use diverse evaluative signals to monitor and adjust decision-making behaviors, adding to our understanding of the different roles that the FEF and caudate nucleus play in a diversity of decision-related computations.

Oscillatory Waveform Shape and Temporal Spike Correlations Differ across Bat Frontal and Auditory Cortex.

Neural oscillations are associated with diverse computations in the mammalian brain. The waveform shape of oscillatory activity measured in the cortex relates to local physiology and can be informative about aberrant or dynamically changing states. However, how waveform shape differs across distant yet functionally and anatomically related cortical regions is largely unknown. In this study, we capitalize on simultaneous recordings of local field potentials (LFPs) in the auditory and frontal cortices of awake, male Carollia perspicillata bats to examine, on a cycle-by-cycle basis, waveform shape differences across cortical regions. We find that waveform shape differs markedly in the fronto-auditory circuit even for temporally correlated rhythmic activity in comparable frequency ranges (i.e., in the delta and gamma bands) during spontaneous activity. In addition, we report consistent differences between areas in the variability of waveform shape across individual cycles. A conceptual model predicts higher spike-spike and spike-LFP correlations in regions with more asymmetric shapes, a phenomenon that was observed in the data: spike-spike and spike-LFP correlations were higher in the frontal cortex. The model suggests a relationship between waveform shape differences and differences in spike correlations across cortical areas. Altogether, these results indicate that oscillatory activity in the frontal and auditory cortex possesses distinct dynamics related to the anatomical and functional diversity of the fronto-auditory circuit.

Encoding of 2D Self-Centered Plans and World-Centered Positions in the Rat Frontal Orienting Field.

The neural mechanisms of motor planning have been extensively studied in rodents. Preparatory activity in the frontal cortex predicts upcoming choice, but limitations of typical tasks have made it challenging to determine whether the spatial information is in a self-centered direction reference frame or a world-centered position reference frame. Here, we trained male rats to make delayed visually guided orienting movements to six different directions, with four different target positions for each direction, which allowed us to disentangle direction versus position tuning in neural activity. We recorded single unit activity from the rat frontal orienting field (FOF) in the secondary motor cortex, a region involved in planning orienting movements. Population analyses revealed that the FOF encodes two separate 2D maps of space. First, a 2D map of the planned and ongoing movement in a self-centered direction reference frame. Second, a 2D map of the animal's current position on the port wall in a world-centered reference frame. Thus, preparatory activity in the FOF represents self-centered upcoming movement directions, but FOF neurons multiplex both self- and world-reference frame variables at the level of single neurons. Neural network model comparison supports the view that despite the presence of world-centered representations, the FOF receives the target information as self-centered input and generates self-centered planning signals.

A special role for anterior cingulate cortex, but not orbitofrontal cortex or basolateral amygdala, in choices involving information.

Subjects are often willing to pay a cost for information. In a procedure that promotes paradoxical choices, animals choose between a richer option followed by a cue that is rewarded 50% of the time (No Info) vs. a leaner option followed by one of two cues that signal certain outcomes: one always rewarded (100%) and the other never rewarded, 0% (Info). Since decisions involve comparing the subjective value of options after integrating all their features, preference for information may rely on cortico-amygdalar circuitry. To test this, male and female rats were prepared with bilateral inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in the anterior cingulate cortex, orbitofrontal cortex, basolateral amygdala, or null virus (control). We inhibited these regions after stable preference was acquired. We found that inhibition of the anterior cingulate cortex destabilized choice preference in female rats without affecting latency to choose or response rate to cues. A logistic regression fit revealed that previous choice predicted current choice in all conditions, however previously rewarded Info trials strongly predicted preference in all conditions except in female rats following anterior cingulate cortex inhibition. The results reveal a causal, sex-dependent role for the anterior cingulate cortex in decisions involving information.

Dorsomedial frontal cortex damage impairs error-based, but not reinforcement-based motor learning in humans.

We adapt our movements to new and changing environments through multiple processes. Sensory error-based learning counteracts environmental perturbations that affect the sensory consequences of movements. Sensory errors also cause the upregulation of reflexes and muscle co-contraction. Reinforcement-based learning enhances the selection of movements that produce rewarding outcomes. Although some findings have identified dissociable neural substrates of sensory error- and reinforcement-based learning, correlative methods have implicated dorsomedial frontal cortex in both. Here, we tested the causal contributions of dorsomedial frontal to adaptive motor control, studying people with chronic damage to this region. Seven human participants with focal brain lesions affecting the dorsomedial frontal and 20 controls performed a battery of arm movement tasks. Three experiments tested: (i) the upregulation of visuomotor reflexes and muscle co-contraction in response to unpredictable mechanical perturbations, (ii) sensory error-based learning in which participants learned to compensate predictively for mechanical force-field perturbations, and (iii) reinforcement-based motor learning based on binary feedback in the absence of sensory error feedback. Participants with dorsomedial frontal damage were impaired in the early stages of force field adaptation, but performed similarly to controls in all other measures. These results provide evidence for a specific and selective causal role for the dorsomedial frontal in sensory error-based learning.

Fractionating difficulty during sentence comprehension using functional neuroimaging.

Sentence comprehension is highly practiced and largely automatic, but this belies the complexity of the underlying processes. We used functional neuroimaging to investigate garden-path sentences that cause difficulty during comprehension, in order to unpack the different processes used to support sentence interpretation. By investigating garden-path and other types of sentences within the same individuals, we functionally profiled different regions within the temporal and frontal cortices in the left hemisphere. The results revealed that different aspects of comprehension difficulty are handled by left posterior temporal, left anterior temporal, ventral left frontal, and dorsal left frontal cortices. The functional profiles of these regions likely lie along a spectrum of specificity to generality, including language-specific processing of linguistic representations, more general conflict resolution processes operating over linguistic representations, and processes for handling difficulty in general. These findings suggest that difficulty is not unitary and that there is a role for a variety of linguistic and non-linguistic processes in supporting comprehension.

SELENBP1 overexpression in the prefrontal cortex underlies negative symptoms of schizophrenia.

The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.

Mothers and fathers show different neural synchrony with their children during shared experiences.

Parent-child shared experiences has an important influence on social development in children although contributions of mothers and fathers may differ. Neural synchronicity occurs between mothers and fathers and their children during social interactions but it is unclear whether they differ in this respect. We used data from simultaneous fNIRS hyperscanning in mothers (n = 33) and fathers (n = 29) and their children (3-4 years) to determine different patterns and strengths of neural synchronization in the frontal cortex during co-viewing of videos or free-play. Mothers showed greater synchrony with child than fathers during passive viewing of videos and the synchronization was positively associated with video complexity and negatively associated with parental stress. During play interactions, mothers showed more controlling behaviors over their child and greater evidence for joint gaze and joint imitation play with child whereas fathers spent more time gazing at other things. In addition, different aspects of child communication promoted neural synchrony between mothers and fathers and child during active play interactions. Overall, our findings indicate greater neural and behavioral synchrony between mothers than fathers and young children during passive or active shared experiences, although for both it was weakened by parental distress and child difficulty.

A perspective on epigenomic aging processes in the human brain and their plasticity in patients with mental disorders - a systematic review.

The debate surrounding nature versus nurture remains a central question in neuroscience, psychology, and in psychiatry, holding implications for both aging processes and the etiology of mental illness. Epigenetics can serve as a bridge between genetic predisposition and environmental influences, thus offering a potential avenue for addressing these questions. Epigenetic clocks, in particular, offer a theoretical framework for measuring biological age based on DNA methylation signatures, enabling the identification of disparities between biological and chronological age. This structured review seeks to consolidate current knowledge regarding the relationship between mental disorders and epigenetic age within the brain. Through a comprehensive literature search encompassing databases such as EBSCO, PubMed, and ClinicalTrials.gov, relevant studies were identified and analyzed. Studies that met inclusion criteria were scrutinized, focusing on those with large sample sizes, analyses of both brain tissue and blood samples, investigation of frontal cortex markers, and a specific emphasis on schizophrenia and depressive disorders. Our review revealed a paucity of significant findings, yet notable insights emerged from studies meeting specific criteria. Studies characterized by extensive sample sizes, analysis of brain tissue and blood samples, assessment of frontal cortex markers, and a focus on schizophrenia and depressive disorders yielded particularly noteworthy results. Despite the limited number of significant findings, these studies shed light on the complex interplay between epigenetic aging and mental illness. While the current body of literature on epigenetic aging in mental disorders presents limited significant findings, it underscores the importance of further research in this area. Future studies should prioritize large sample sizes, comprehensive analyses of brain tissue and blood samples, exploration of specific brain regions such as the frontal cortex, and a focus on key mental disorders. Such endeavors will contribute to a deeper understanding of the relationship between epigenetic aging and mental illness, potentially informing novel diagnostic and therapeutic approaches.

In situ analysis of neuronal injury and neuroinflammation during HIV-1 infection.

BACKGROUND: Since the introduction of combination antiretroviral therapy (cART) the brain has become an important human immunodeficiency virus (HIV) reservoir due to the relatively low penetration of many drugs utilized in cART into the central nervous system (CNS). Given the inherent limitations of directly assessing acute HIV infection in the brains of people living with HIV (PLWH), animal models, such as humanized mouse models, offer the most effective means of studying the effects of different viral strains and their impact on HIV infection in the CNS. To evaluate CNS pathology during HIV-1 infection in the humanized bone marrow/liver/thymus (BLT) mouse model, a histological analysis was conducted on five CNS regions, including the frontal cortex, hippocampus, striatum, cerebellum, and spinal cord, to delineate the neuronal (MAP2ab, NeuN) and neuroinflammatory (GFAP, Iba-1) changes induced by two viral strains after 2 weeks and 8 weeks post-infection. RESULTS: Findings reveal HIV-infected human cells in the brain of HIV-infected BLT mice, demonstrating HIV neuroinvasion. Further, both viral strains, HIV-1JR-CSF and HIV-1CH040, induced neuronal injury and astrogliosis across all CNS regions following HIV infection at both time points, as demonstrated by decreases in MAP2ab and increases in GFAP fluorescence signal, respectively. Importantly, infection with HIV-1JR-CSF had more prominent effects on neuronal health in specific CNS regions compared to HIV-1CH040 infection, with decreasing number of NeuN+ neurons, specifically in the frontal cortex. On the other hand, infection with HIV-1CH040 demonstrated more prominent effects on neuroinflammation, assessed by an increase in GFAP signal and/or an increase in number of Iba-1+ microglia, across CNS regions. CONCLUSION: These findings demonstrate that CNS pathology is widespread during acute HIV infection. However, neuronal loss and the magnitude of neuroinflammation in the CNS is strain dependent indicating that strains of HIV cause differential CNS pathologies.

RNA editing regulates glutamatergic synapses in the frontal cortex of a molecular subtype of Amyotrophic Lateral Sclerosis.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a highly heterogenous neurodegenerative disorder that primarily affects upper and lower motor neurons, affecting additional cell types and brain regions. Underlying molecular mechanisms are still elusive, in part due to disease heterogeneity. Molecular disease subtyping through integrative analyses including RNA editing profiling is a novel approach for identification of molecular networks involved in pathogenesis. METHODS: We aimed to highlight the role of RNA editing in ALS, focusing on the frontal cortex and the prevalent molecular disease subtype (ALS-Ox), previously determined by transcriptomic profile stratification. We established global RNA editing (editome) and gene expression (transcriptome) profiles in control and ALS-Ox cases, utilizing publicly available RNA-seq data (GSE153960) and an in-house analysis pipeline. Functional annotation and pathway analyses identified molecular processes affected by RNA editing alterations. Pearson correlation analyses assessed RNA editing effects on expression. Similar analyses on additional ALS-Ox and control samples (GSE124439) were performed for verification. Targeted re-sequencing and qRT-PCR analysis targeting CACNA1C, were performed using frontal cortex tissue from ALS and control samples (n = 3 samples/group). RESULTS: We identified reduced global RNA editing in the frontal cortex of ALS-Ox cases. Differentially edited transcripts are enriched in synapses, particularly in the glutamatergic synapse pathway. Bioinformatic analyses on additional ALS-Ox and control RNA-seq data verified these findings. We identified increased recoding at the Q621R site in the GRIK2 transcript and determined positive correlations between RNA editing and gene expression alterations in ionotropic receptor subunits GRIA2, GRIA3 and the CACNA1C transcript, which encodes the pore forming subunit of a post-synaptic L-type calcium channel. Experimental data verified RNA editing alterations and editing-expression correlation in CACNA1C, highlighting CACNA1C as a target for further study. CONCLUSIONS: We provide evidence on the involvement of RNA editing in the frontal cortex of an ALS molecular subtype, highlighting a modulatory role mediated though recoding and gene expression regulation on glutamatergic synapse related transcripts. We report RNA editing effects in disease-related transcripts and validated editing alterations in CACNA1C. Our study provides targets for further functional studies that could shed light in underlying disease mechanisms enabling novel therapeutic approaches.

Altered functional connectivity of primary olfactory cortex-hippocampus-frontal cortex in subjective cognitive decline during odor stimulation.

Subjective cognitive decline (SCD) is a high-risk population in the preclinical stage of Alzheimer's disease (AD), and olfactory dysfunction is a risk factor for dementia progression. The present study aimed to explore the patterns of functional connectivity (FC) changes in the olfactory neural circuits during olfactory stimulation in SCD subjects. A total of 56 SCD subjects and 56 normal controls (NCs) were included. All subjects were assessed with a cognitive scale, an olfactory behavior test, and olfactory task-based functional magnetic resonance imaging scanning. The FC differences in olfactory neural circuits between the two groups were analyzed by the generalized psychophysiological interaction. Additionally, we calculated and compared the activation of brain regions within the olfactory neural circuits during odor stimulation, the volumetric differences in brain regions showing FC differences between groups, and the correlations between neuroimaging indicators and olfactory behavioral and cognitive scale scores. During odor stimulation, the FC between the bilateral primary olfactory cortex (bPOC) and the right hippocampus in the SCD group was significantly reduced; while the FC between the right hippocampus and the right frontal cortex was significantly increased in the SCD group. The bPOC of all subjects showed significant activation, but no significant difference in activation between groups was found. No significant differences were observed in the volume of the brain regions within the olfactory neural circuits or in olfactory behavior between groups. The volume of the bPOC and right frontal cortex was significantly positively correlated with olfactory identification, and the volume of the right frontal cortex and right hippocampus was significantly correlated with cognitive functions. Furthermore, a significant correlation between the activation of bPOC and the olfactory threshold was found in the whole cohort. These results suggested that while the structure of the olfactory neural circuits and olfactory behavior in SCD subjects remained stable, there were significant changes observed in the FC of the olfactory neural circuits (specifically, the POC-hippocampus-frontal cortex neural circuits) during odor stimulation. These findings highlight the potential of FC alterations as sensitive imaging markers for identifying high-risk individuals in the early stage of AD.

Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome.

We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer's disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolated from postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.