Population Of Pyramidal Neurons Research Articles

Adenosine Metabolism Pathway Alterations in Frontal Cortical Neurons in Schizophrenia.

Schizophrenia is a neuropsychiatric illness characterized by altered neurotransmission, in which adenosine, a modulator of glutamate and dopamine, plays a critical role that is relatively unexplored in the human brain. In the present study, postmortem human brain tissue from the anterior cingulate cortex (ACC) of individuals with schizophrenia (n = 20) and sex- and age-matched control subjects without psychiatric illness (n = 20) was obtained from the Bronx-Mount Sinai NIH Brain and Tissue Repository. Enriched populations of ACC pyramidal neurons were isolated using laser microdissection (LMD). The mRNA expression levels of six key adenosine pathway components-adenosine kinase (ADK), equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), ectonucleoside triphosphate diphosphohydrolases 1 and 3 (ENTPD1 and ENTPD3), and ecto-5'-nucleotidase (NT5E)-were quantified using real-time PCR (qPCR) in neurons from these individuals. No significant mRNA expression differences were observed between the schizophrenia and control groups (p > 0.05). However, a significant sex difference was found in ADK mRNA expression, with higher levels in male compared with female subjects (Mann-Whitney U = 86; p < 0.05), a finding significantly driven by disease (t(17) = 3.289; p < 0.05). Correlation analyses also demonstrated significant associations (n = 12) between the expression of several adenosine pathway components (p < 0.05). In our dementia severity analysis, ENTPD1 mRNA expression was significantly higher in males in the "mild" clinical dementia rating (CDR) bin compared with males in the "none" CDR bin (F(2, 13) = 5.212; p < 0.05). Lastly, antipsychotic analysis revealed no significant impact on the expression of adenosine pathway components between medicated and non-medicated schizophrenia subjects (p > 0.05). The observed sex-specific variations and inter-component correlations highlight the value of investigating sex differences in disease and contribute to the molecular basis of schizophrenia's pathology.

A master regulator of opioid reward in the ventral prefrontal cortex.

In addition to their intrinsic rewarding properties, opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping in mice to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone. Connectomic profiling revealed that DPn neurons innervate the parabrachial nucleus (PBn). Spatial and single-nuclei transcriptomics resolved a population of PBn-projecting pyramidal neurons in the DPn that express μ-opioid receptors (μORs). Disrupting μOR signaling in the DPn switched oxycodone from rewarding to aversive and exacerbated the severity of opioid withdrawal. These findings identify the DPn as a key substrate for the abuse liability of opioids.

Dysregulated Transcript Expression but Not Function of the Glutamate Transporter EAAT2 in the Dorsolateral Prefrontal Cortex in Schizophrenia.

Schizophrenia (SCZ) is a serious mental illness with complex pathology, including abnormalities in the glutamate system. Glutamate is rapidly removed from the synapse by excitatory amino acid transporters (EAATs). Changes in the expression and localization of the primary glutamate transporter EAAT2 are found in the brain in central nervous system (CNS) disorders including SCZ. We hypothesize that neuronal expression and function of EAAT2 are increased in the frontal cortex in subjects diagnosed with SCZ. EAAT2 protein expression and glutamate transporter function were assayed in synaptosome preparations from the dorsolateral prefrontal cortex (DLPFC) of SCZ subjects and age- and sex-matched nonpsychiatrically ill controls. EAAT2 splice variant transcript expression was assayed in enriched populations of neurons and astrocytes from the DLPFC. Pathway analysis of publicly available transcriptomic datasets was carried out to identify biological changes associated with EAAT2 perturbation in different cell types. We found no significant changes in EAAT2 protein expression or glutamate uptake in the DLPFC in SCZ subjects compared with controls (n = 10/group). Transcript expression of EAAT2 and signaling molecules associated with EAAT2b trafficking (CaMKIIa and DLG1) were significantly altered in enriched populations of astrocytes and pyramidal neurons (P < .05) in SCZ (n = 16/group). These changes were not associated with antipsychotic medications. Pathway analysis also identified cell-type-specific enrichment of biological pathways associated with perturbation of astrocyte (immune pathways) and neuronal (metabolic pathways) EAAT2 expression. Overall, these data support the growing body of evidence for the role of dysregulation of the glutamate system in the pathophysiology of SCZ.

Adenosine Receptor mRNA Expression in Frontal Cortical Neurons in Schizophrenia.

Schizophrenia is a devastating neuropsychiatric disorder associated with the dysregulation of glutamate and dopamine neurotransmitter systems. The adenosine system is an important neuroregulatory system in the brain that modulates glutamate and dopamine signaling via the ubiquitously expressed adenosine receptors; however, adenosine A1 and A2A receptor (A1R and A2AR) mRNA expression is poorly understood in specific cell subtypes in the frontal cortical brain regions implicated in this disorder. In this study, we assayed A1R and A2AR mRNA expression via qPCR in enriched populations of pyramidal neurons, which were isolated from postmortem anterior cingulate cortex (ACC) tissue from schizophrenia (n = 20) and control (n = 20) subjects using laser microdissection (LMD). A1R expression was significantly increased in female schizophrenia subjects compared to female control subjects (t(13) = -4.008, p = 0.001). A1R expression was also significantly decreased in female control subjects compared to male control subjects, suggesting sex differences in basal A1R expression (t(17) = 2.137, p = 0.047). A significant, positive association was found between dementia severity (clinical dementia rating (CDR) scores) and A2AR mRNA expression (Spearman's r = 0.424, p = 0.009). A2AR mRNA expression was significantly increased in unmedicated schizophrenia subjects, suggesting that A2AR expression may be normalized by chronic antipsychotic treatment (F(1,14) = 9.259, p = 0.009). Together, these results provide novel insights into the neuronal expression of adenosine receptors in the ACC in schizophrenia and suggest that receptor expression changes may be sex-dependent and associated with cognitive decline in these subjects.

HNN-core: A Python software for cellular and circuit-level interpretation of human MEG/EEG.

HNN-core is a library for circuit and cellular level interpretation of non-invasive human magneto-/electro-encephalography (MEG/EEG) data. It is based on the Human Neocortical Neurosolver (HNN) software (Neymotin et al., 2020), a modeling tool designed to simulate multiscale neural mechanisms generating current dipoles in a localized patch of neocortex. HNN's foundation is a biophysically detailed neural network representing a canonical neocortical column containing populations of pyramidal and inhibitory neurons together with layer-specific exogenous synaptic drive (Figure 1 left). In addition to simulating network-level interactions, HNN produces the intracellular currents in the long apical dendrites of pyramidal cells across the cortical layers known to be responsible for macroscopic current dipole generation.

In Utero Electroporated Neurons for Medium-Throughput Screening of Compounds Regulating Neuron Morphology.

Several neurodevelopmental disorders are associated with increased mTOR activity that results in pathogenic neuronal dysmorphogenesis (i.e., soma and dendrite overgrowth), leading to circuit alterations associated with epilepsy and neurologic disabilities. Although an mTOR analog is approved for the treatment of epilepsy in one of these disorders, it has limited efficacy and is associated with a wide range of side effects. There is a need to develop novel agents for the treatment of mTOR-pathway related disorders. Here, we developed a medium-throughput phenotypic assay to test drug efficacy on neurite morphogenesis of mouse neurons in a hyperactive mTOR condition. Our assay involved in utero electroporation (IUE) of a selective population of cortical pyramidal neurons with a plasmid encoding the constitutively active mTOR activator, Rheb, and tdTomato. Labeled neurons from the somatosensory cortex (SSC) were cultured onto 96-well plates and fixed at various days in vitro or following Torin 1 treatment. Automated systems were used for image acquisition and neuron morphologic measurements. We validated our automated approach using traditional manual methods of neuron morphologic assessment. Both automated and manual analyses showed increased neurite length and complexity over time, and decreased neurite overgrowth and soma size with Torin 1. These data validate the accuracy of our automated approach that takes hours compared with weeks when using traditional manual methods. Taken together, this assay can be scaled to screen 32 compounds simultaneously in two weeks, highlighting its robustness and efficiency for medium-throughput screening of candidate therapeutics on a defined population of wild-type or diseased neurons.

Divergent projections of the prelimbic cortex mediate autism- and anxiety-like behaviors

The comorbidity of autism spectrum disorder and anxiety is common, but the underlying circuitry is poorly understood. Here, Tmem74-/- mice showed autism- and anxiety-like behaviors along with increased excitability of pyramidal neurons (PNs) in the prelimbic cortex (PL), which were reversed by Tmem74 re-expression and chemogenetic inhibition in PNs of the PL. To determine the underlying circuitry, we performed conditional deletion of Tmem74 in the PNs of PL of mice, and we found that alterations in the PL projections to fast-spiking interneurons (FSIs) in the dorsal striatum (dSTR) (PLPNs–dSTRFSIs) mediated the hyperexcitability of FSIs and autism-like behaviors and that alterations in the PL projections to the PNs of the basolateral amygdaloid nucleus (BLA) (PLPNs–BLAPNs) mediated the hyperexcitability of PNs and anxiety-like behaviors. However, the two populations of PNs in the PL had different spatial locations, optogenetic manipulations revealed that alterations in the activity in the PL–dSTR or PL–BLA circuits led to autism- or anxiety-like behaviors, respectively. Collectively, these findings highlight that the hyperactivity of the two populations of PNs in the PL mediates autism and anxiety comorbidity through the PL–dSTR and PL–BLA circuits, which may lead to the development of new therapeutics for the autism and anxiety comorbidity.

Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model

Tau protein pathology is a hallmark of many neurodegenerative diseases, including Alzheimer's Disease or frontotemporal dementia. Synaptic dysfunction and abnormal visual evoked potentials have been reported in murine models of tauopathy, but little is known about the state of the network activity on a single neuronal level prior to brain atrophy. In the present study, oscillatory rhythms and single-cell calcium activity of primary visual cortex pyramidal neuron population were investigated in basal and light evoked states in the rTg4510 tauopathy mouse model prior to neurodegeneration. We found a decrease in their responsivity and overall activity which was insensitive to GABAergic modulation. Despite an enhancement of basal state coactivation of cortical pyramidal neurons, a loss of input-output synchronicity was observed. Dysfunction of cortical pyramidal function was also reflected in a reduction of basal theta oscillations and enhanced susceptibility to a sub-convulsive dose of pentylenetetrazol in rTg4510 mice. Our results unveil impairments in visual cortical pyramidal neuron processing and define aberrant oscillations as biomarker candidates in early stages of neurodegenerative tauopathies.

Prenatal reduction of E14.5 embryonically fate-mapped pyramidal neurons in a mouse model of autism.

Although several observations suggest that the constitutive biological, genetic or physiological changes leading to autism spectrum disorders (ASD) start in utero, their early impact on the number and density of neurons in the brain remains unknown. Using genetic fate mapping associated with the immunollabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO) clearing method we identified and counted a selective population of neocortical and hippocampal pyramidal neurons in the in utero valproate (VPA) mouse model of autism. We report that 1 day before birth, the number of pyramidal neurons born at E14.5 in the neocortex and hippocampus of VPA mice is smaller than in age-matched controls. VPA also induced a reduction of the neocortical-but not hippocampal-volume 1 day before birth. Interestingly, VPA mice present an increase in both neocortical and hippocampal volumes 2days after birth compared with controls. These results suggest that the VPA-exposed hippocampus and neocortex differ substantially from controls during the highly complex perinatal period, and specially 1 day before birth, reflecting the early pathogenesis of ASD.

High-frequency oscillations and sequence generation in two-population models of hippocampal region CA1.

Hippocampal sharp wave/ripple oscillations are a prominent pattern of collective activity, which consists of a strong overall increase of activity with superimposed (140 − 200 Hz) ripple oscillations. Despite its prominence and its experimentally demonstrated importance for memory consolidation, the mechanisms underlying its generation are to date not understood. Several models assume that recurrent networks of inhibitory cells alone can explain the generation and main characteristics of the ripple oscillations. Recent experiments, however, indicate that in addition to inhibitory basket cells, the pattern requires in vivo the activity of the local population of excitatory pyramidal cells. Here, we study a model for networks in the hippocampal region CA1 incorporating such a local excitatory population of pyramidal neurons. We start by investigating its ability to generate ripple oscillations using extensive simulations. Using biologically plausible parameters, we find that short pulses of external excitation triggering excitatory cell spiking are required for sharp/wave ripple generation with oscillation patterns similar to in vivo observations. Our model has plausible values for single neuron, synapse and connectivity parameters, random connectivity and no strong feedforward drive to the inhibitory population. Specifically, whereas temporally broad excitation can lead to high-frequency oscillations in the ripple range, sparse pyramidal cell activity is only obtained with pulse-like external CA3 excitation. Further simulations indicate that such short pulses could originate from dendritic spikes in the apical or basal dendrites of CA1 pyramidal cells, which are triggered by coincident spike arrivals from hippocampal region CA3. Finally we show that replay of sequences by pyramidal neurons and ripple oscillations can arise intrinsically in CA1 due to structured connectivity that gives rise to alternating excitatory pulse and inhibitory gap coding; the latter denotes phases of silence in specific basket cell groups, which induce selective disinhibition of groups of pyramidal neurons. This general mechanism for sequence generation leads to sparse pyramidal cell and dense basket cell spiking, does not rely on synfire chain-like feedforward excitation and may be relevant for other brain regions as well.

Neural Substrates and Models of Omission Responses and Predictive Processes.

Predictive coding theories argue that deviance detection phenomena, such as mismatch responses and omission responses, are generated by predictive processes with possibly overlapping neural substrates. Molecular imaging and electrophysiology studies of mismatch responses and corollary discharge in the rodent model allowed the development of mechanistic and computational models of these phenomena. These models enable translation between human and non-human animal research and help to uncover fundamental features of change-processing microcircuitry in the neocortex. This microcircuitry is characterized by stimulus-specific adaptation and feedforward inhibition of stimulus-selective populations of pyramidal neurons and interneurons, with specific contributions from different interneuron types. The overlap of the substrates of different types of responses to deviant stimuli remains to be understood. Omission responses, which are observed both in corollary discharge and mismatch response protocols in humans, are underutilized in animal research and may be pivotal in uncovering the substrates of predictive processes. Omission studies comprise a range of methods centered on the withholding of an expected stimulus. This review aims to provide an overview of omission protocols and showcase their potential to integrate and complement the different models and procedures employed to study prediction and deviance detection.This approach may reveal the biological foundations of core concepts of predictive coding, and allow an empirical test of the framework’s promise to unify theoretical models of attention and perception.

Control of parallel hippocampal output pathways by amygdalar long-range inhibition.

Projections from the basal amygdala (BA) to the ventral hippocampus (vH) are proposed to provide information about the rewarding or threatening nature of learned associations to support appropriate goal-directed and anxiety-like behaviour. Such behaviour occurs via the differential activity of multiple, parallel populations of pyramidal neurons in vH that project to distinct downstream targets, but the nature of BA input and how it connects with these populations is unclear. Using channelrhodopsin-2-assisted circuit mapping in mice, we show that BA input to vH consists of both excitatory and inhibitory projections. Excitatory input specifically targets BA- and nucleus accumbens-projecting vH neurons and avoids prefrontal cortex-projecting vH neurons, while inhibitory input preferentially targets BA-projecting neurons. Through this specific connectivity, BA inhibitory projections gate place-value associations by controlling the activity of nucleus accumbens-projecting vH neurons. Our results define a parallel excitatory and inhibitory projection from BA to vH that can support goal-directed behaviour.

Electrophysiological Characterization of Regular and Burst Firing Pyramidal Neurons of the Dorsal Subiculum in an Angelman Syndrome Mouse Model

Angelman syndrome (AS) is a debilitating neurogenetic disorder characterized by severe developmental delay, speech impairment, gait ataxia, sleep disturbances, epilepsy, and a unique behavioral phenotype. AS is caused by a microdeletion or mutation in the maternal 15q11-q13 chromosome region containing UBE3A gene. The hippocampus is one of the important brain regions affected in AS mice leading to substantial hippocampal-dependent cognitive and behavioral deficits. Recent studies have suggested an abnormal increase in the α1-Na/K-ATPase (α1-NaKA) in AS mice as the precipitating factor leading to the hippocampal deficits. A subsequent study showed that the hippocampal-dependent behavioral deficits occur as a result of altered calcium (Ca+2) dynamics in the CA1 pyramidal neurons (PNs) caused by the elevated α1-NaKA expression levels in the AS mice. Nonetheless, a causal link between hippocampal deficits and major behavioral phenotypes in AS is still obscure. Subiculum, a region adjacent to the hippocampal CA1 is the major output source of the hippocampus and plays an important role in the transfer of information from the CA1 region to the cortical areas. However, in spite of the robust hippocampal deficits and several known electrophysiological alterations in multiple brain regions in AS mice, the neuronal properties of the subicular neurons were never investigated in these mice. Additionally, subicular function is also implied in many neuropsychiatric disorders such as autism, schizophrenia, Alzheimer’s disease, and epilepsy that share some common features with AS. Therefore, given the importance of the subiculum in these neuropsychiatric disorders and the altered electrophysiological properties of the hippocampal CA1 PNs projecting to the subiculum, we sought to examine the subicular PNs. We performed whole-cell recordings from dorsal subiculum of both WT and AS mice and found three distinct populations of PNs based on their ability to fire bursts or single action potentials following somatic current injection: strong bursting, weak bursting, and regular firing neurons. We found no overall differences in the distribution of these different subicular PN populations among AS and WT controls. However, the different cell types showed distinct alterations in their intrinsic membrane properties. Further, none of these populations were altered in their excitatory synaptic properties. Altogether, our study characterized the different subtypes of PNs in the subicular region of an AS mouse model.

Distinct populations of cortical pyramidal neurons mediate drug reward and aversion

Processing within the anterior cingulate cortex (ACC) is crucial for the patterning of appropriate behavior, and ACC dysfunction following chronic drug use is thought to play a major role in drug addiction. However, cortical pyramidal projection neurons can be subdivided into two major types (intratelencephalic (IT) and pyramidal tract (PT)), with distinct inputs and projection targets, molecular and receptor profiles, morphologies and electrophysiological properties. Yet, how each of these cell populations modulate behavior related to addiction is unknown. We demonstrate that PT neurons regulate the positive features of a drug experience whereas IT neurons regulate the negative features. These findings support a revised theory of cortical function in addiction, with distinct cells and circuits mediating reward and aversion.

Fhod3 Controls the Dendritic Spine Morphology of Specific Subpopulations of Pyramidal Neurons in the Mouse Cerebral Cortex.

Changes in the shape and size of the dendritic spines are critical for synaptic transmission. These morphological changes depend on dynamic assembly of the actin cytoskeleton and occur differently in various types of neurons. However, how the actin dynamics are regulated in a neuronal cell type-specific manner remains largely unknown. We show that Fhod3, a member of the formin family proteins that mediate F-actin assembly, controls the dendritic spine morphogenesis of specific subpopulations of cerebrocortical pyramidal neurons. Fhod3 is expressed specifically in excitatory pyramidal neurons within layers II/III and V of restricted areas of the mouse cerebral cortex. Immunohistochemical and biochemical analyses revealed the accumulation of Fhod3 in postsynaptic spines. Although targeted deletion of Fhod3 in the brain did not lead to any defects in the gross or histological appearance of the brain, the dendritic spines in pyramidal neurons within presumptive Fhod3-positive areas were morphologically abnormal. In primary cultures prepared from the Fhod3-depleted cortex, defects in spine morphology were only detected in Fhod3 promoter-active cells, a small population of pyramidal neurons, and not in Fhod3 promoter-negative pyramidal neurons. Thus, Fhod3 plays a crucial role in dendritic spine morphogenesis only in a specific population of pyramidal neurons in a cell type-specific manner.

Stability of motor cortex network states during learning-associated neural reorganizations.

A substantial reorganization of neural activity and neuron-to-movement relationship in motor cortical circuits accompanies the emergence of reproducible movement patterns during motor learning. Little is known about how this tempest of neural activity restructuring impacts the stability of network states in recurrent cortical circuits. To investigate this issue, we reanalyzed data in which we recorded for 14 days via population calcium imaging the activity of the same neural populations of pyramidal neurons in layer 2/3 and layer 5 of forelimb motor and premotor cortex in mice during the daily learning of a lever-press task. We found that motor cortex network states remained stable with respect to the critical network state during the extensive reorganization of both neural population activity and its relation to lever movement throughout learning. Specifically, layer 2/3 cortical circuits unceasingly displayed robust evidence for operating at the critical network state, a regime that maximizes information capacity and transmission and provides a balance between network robustness and flexibility. In contrast, layer 5 circuits operated away from the critical network state for all 14 days of recording and learning. In conclusion, this result indicates that the wide-ranging malleability of synapses, neurons, and neural connectivity during learning operates within the constraint of a stable and layer-specific network state regarding dynamic criticality, and suggests that different cortical layers operate under distinct constraints because of their specialized goals.NEW & NOTEWORTHY The neural activity reorganizes throughout motor learning, but how this reorganization impacts the stability of network states is unclear. We used two-photon calcium imaging to investigate how the network states in layer 2/3 and layer 5 of forelimb motor and premotor cortex are modulated by motor learning. We show that motor cortex network states are layer-specific and constant regarding criticality during neural activity reorganization, and suggests that layer-specific constraints could be motivated by different functions.

A Pipeline using Bilateral In Utero Electroporation to Interrogate Genetic Influences on Rodent Behavior.

As genome-wide association studies shed light on the heterogeneous genetic underpinnings of many neurological diseases, the need to study the contribution of specific genes to brain development and function increases. Relying on mouse models to study the role of specific genetic manipulations is not always feasible since transgenic mouse lines are quite costly and many novel disease-associated genes do not yet have commercially available genetic lines. Additionally, it can take years of development and validation to create a mouse line. In utero electroporation offers a relatively quick and easy method to manipulate gene expression in a cell-type specific manner in vivo that only requires developing a DNA plasmid to achieve a particular genetic manipulation. Bilateral in utero electroporation can be used to target large populations of frontal cortex pyramidal neurons. Combining this gene transfer method with behavioral approaches allows one to study the effects of genetic manipulations on the function of prefrontal cortex networks and the social behavior of juvenile and adult mice.

Perspective on the Multiple Pathways to Changing Brain States.

In this review article, we highlight several disparate ideas that are linked to changes in brain state (i.e., sleep to arousal, Down to Up, synchronized to de-synchronized). In any discussion of the brain state, we propose that the cortical pyramidal neuron has a central position. EEG recordings, which typically assess brain state, predominantly reflect the activity of cortical pyramidal neurons. This means that the dominant rhythmic activity that characterizes a particular brain state ultimately has to manifest globally across the pyramidal neuron population. During state transitions, it is the long-range connectivity of these neurons that broadcast the resultant changes in activity to many subcortical targets. Structures like the thalamus, brainstem/hypothalamic neuromodulatory systems, and respiratory systems can also strongly influence brain state, and for many decades we have been uncovering bidirectional pathways that link these structures to state changes in the cerebral cortex. More recently, movement and active behaviors have emerged as powerful drivers of state changes. Each of these systems involve different circuits distributed across the brain. Yet, for a system-wide change in brain state, there must be a collaboration between these circuits that reflects and perhaps triggers the transition between brain states. As we expand our understanding of how brain state changes, our current challenge is to understand how these diverse sets of circuits and pathways interact to produce the changes observed in cortical pyramidal neurons.

Human brain neurons express a novel splice variant of excitatory amino acid transporter 5 (hEAAT5v).

Excitatory amino acid transporter 5 (EAAT5) is a protein that is known to be alternately spliced and to be abundantly expressed in the retina by populations of neurons including photoreceptors and bipolar cells. EAAT5 acts as a slow glutamate transporter and also as glutamate-gated chloride channel, the chloride conductance being large enough for EAAT5 to serve functionally as an "inhibitory" glutamate receptor. However, there has been a long-standing view that the classically spliced form of EAAT5 is not abundant or widespread in the brain and so it has not been extensively investigated in the literature. We recently identified a human-specific splicing form of EAAT5 that was not expressed by rodents but was shown to be a functional glutamate transporter. We have examined the expression of this form of EAAT5, hEAAT5v at the mRNA, and protein level in human brain, and show that populations of human cortical pyramidal neurons and cerebellar Purkinje cells show significant expression of hEAAT5v. Accordingly, we infer that EAAT5 may well be a player in modulating neuronal function in the human brain and propose that its localization in both glutamatergic and GABAergic neurons could be compatible with a role in influencing intracellular chloride and thereby neuronal parameters such as membrane potential rather than acting as a presynaptic glutamate transporter.

Biased Connectivity of Brain-wide Inputs to Ventral Subiculum Output Neurons

SummaryThe ventral subiculum (vS) of the mouse hippocampus coordinates diverse behaviors through heterogeneous populations of pyramidal neurons that project to multiple distinct downstream regions. Each of these populations of neurons is proposed to integrate a unique combination of thousands of local and long-range synaptic inputs, but the extent to which this occurs remains unknown. To address this, we employ monosynaptic rabies tracing to study the input-output relationship of vS neurons. Analysis of brain-wide inputs reveals quantitative input differences that could be explained by a combination of both the identity of the downstream target and the spatial location of the postsynaptic neurons within vS. These results support a model of combined topographical and output-defined connectivity of vS inputs. Overall, we reveal prominent heterogeneity in brain-wide inputs to the vS parallel output circuitry, providing a basis for the selective control of individual projections during behavior.