RESUMEN

Dorsal neural tube-derived retinoic acid promotes the end of neural crest production and transition into a definitive roof plate. Here we analyze how this impacts the segregation of central and peripheral lineages, a process essential for tissue patterning and function. Localized in-ovo inhibition in quail embryos of retinoic acid activity followed by single cell transcriptomics unraveled a comprehensive list of differentially expressed genes relevant to these processes. Importantly, progenitors co-expressed neural crest, roof plate and dI1 interneuron markers indicating a failure in proper lineage segregation. Furthermore, separation between roof plate and dI1 interneurons is mediated by Notch activity downstream of retinoic acid, highlighting their critical role in establishing the roof plate-dI1 boundary. Within the peripheral branch, where absence of retinoic acid resulted in neural crest production and emigration extending into the roof plate stage, sensory progenitors failed to separate from melanocytes leading to formation of a common glia-melanocyte cell with aberrant migratory patterns. Together, the implementation of scRNA sequencing facilitated the discovery and characterization of a molecular mechanism responsible for the segregation of dorsal neural fates during development.

RESUMEN

Despite much progress in identifying risk genes for polygenic brain disorders, their core pathogenic mechanisms remain poorly understood. In particular, functions of many proteins encoded by schizophrenia risk genes appear diverse and unrelated, complicating the efforts to establish the causal relationship between genes and behavior. Using various mouse lines, recent studies indicate that alterations of parvalbumin-positive (PV+) GABAergic interneurons can lead to schizophrenia-like behavior. PV+ interneurons display fast spiking and contribute to excitation-inhibition balance and network oscillations via feedback and feedforward inhibition. Here, we first summarize different lines of genetically modified mice that display motor, cognitive, emotional, and social impairments used to model schizophrenia and related mental disorders. We highlight ten genes, encoding either a nuclear, cytosolic, or membrane protein. Next, we discuss their functional relationship in regulating fast spiking and other aspects of PV+ interneurons and in the context of other domains of schizophrenia. Future investigations combining behavioral genetics and cell biology should elucidate functional relationships among risk genes to identify the core pathogenic mechanisms underlying polygenic brain disorders.

RESUMEN

BACKGROUND: Stress has become a prevalent public health concern, contributing to the rising prevalence of psychiatric disorders. Understanding stress impact considering critical variables, such as age, sex, and individual differences, is of utmost importance for developing effective intervention strategies. METHODS: Stress effects (daily footshocks for ten days) during adolescence (postnatal day, PND31-40) and adulthood (PND65-74) were investigated on behavioral outcomes and parvalbumin (PV)-expressing GABAergic interneurons and their associated perineuronal nets (PNNs) in the prefrontal cortex (PFC) of male and female mice five weeks post-stress. RESULTS: In adulthood, adolescent stress induced behavioral alterations in male mice, including anxiety-like behaviors, social deficits, cognitive impairments, and altered dopamine system responsivity. Applying integrated behavioral z-score analysis, we identified sex-specific differences in response to adolescent stress, with males displaying greater vulnerability than females. Furthermore, adolescent-stressed male mice showed a decrease PV+ and PNN+ cell numbers and PV+/PNN+ colocalization, while in females, adolescent stress reduced prefrontal PV+/PNN+ colocalization in the PFC. Further analysis identified distinct behavioral clusters, with certain females demonstrating resilience to adolescent stress-induced deficits in sociability and PV+ cell number. Adult stress in male and female mice did not cause long-lasting changes in behavior and PV+ and PNN+ cell number. CONCLUSION: Our findings indicate that the timing of stress, sex and individual variabilities seem to be determinants for the development of behavioral changes associated with psychiatric disorders, particularly in male mice during adolescence.

RESUMEN

Adolescence is an important phase for the structural and functional development of the brain. The immaturity of adolescent brain development is associated with high susceptibility to exogenous disturbances, including alcohol. In this study, the acquisition of conditioned place preference (CPP) in adolescent mice by alcohol (2 g/kg) and the parvalbumin-positive interneurons (PV+ interneurons), oligodendrocyte lineage cells (OPCs), and myelination in the medial prefrontal cortex (mPFC) were assessed. We aim to determine the age- and subregional-specificity of the effects of alcohol. Alcohol (2 g/kg) was injected intraperitoneally on even days, and saline was injected intraperitoneally on odd days. The control group received a continuous intraperitoneal injection with saline. Differences in alcohol-induced CPP acquisition were assessed, followed by immunohistochemical staining. The results showed a pronounced CPP acquisition in 4- and 5-week-old mice. In the mPFC, there were reduced PV+ interneurons and OPCs in 3-week-old mice and reduced oligodendrocyte numbers in 4-week-old mice. The 5-week-old mice showed impaired myelination and a decrease in the number of PV+ interneurons, mature oligodendrocytes, and OPCs in the mPFC. Since the alterations in 5-week-old mice are more pronounced, we further explored the mPFC-associated subregional-specificity. In the alcohol-exposed mice, the oligodendrocyte numbers were decreased in the anterior cingulate cortex (ACC), PV+ interneuron numbers were declined in the prelimbic cortex (PL), and the number of oligodendrocytes, PV+ interneurons, and OPCs was also decreased with impaired myelination in the infralimbic cortex (IL). Our data suggest that adolescent alcohol exposure notably affected the acquisition of CPP, myelin formation, and the counts of PV+ interneurons, mature oligodendrocytes, and OPCs in the mPFC in 5-week-old mice. Also, the IL subregion was the worst-affected subregion of the mPFC in alcohol-exposed 5-week-old mice. It reveals that the effects of alcohol on adolescence and its mPFC myelination show obvious age- and subregional-specificity.

RESUMEN

Different speeds of locomotion require heterogeneous spinal populations, but a common mode of rhythm generation is presumed to exist. Here, we explore the cellular versus synaptic origins of spinal rhythmicity at different speeds by performing electrophysiological recordings from premotor excitatory interneurons in larval zebrafish. Chx10-labeled V2a neurons are divided into at least two morphological subtypes proposed to play distinct roles in timing and intensity control. Consistent with distinct rhythm generating and output patterning functions within the spinal V2a population, we find that descending subtypes are recruited exclusively at slow or fast speeds and exhibit intrinsic cellular properties suitable for rhythmogenesis at those speeds, while bifurcating subtypes are recruited more reliably at all speeds and lack appropriate rhythmogenic cellular properties. Unexpectedly, however, phasic firing patterns during locomotion in rhythmogenic and non-rhythmogenic V2a neurons alike are best explained by distinct modes of synaptic inhibition linked to cell type and speed. At fast speeds reciprocal inhibition in descending V2a neurons supports phasic firing, while recurrent inhibition in bifurcating V2a neurons helps pattern motor output. In contrast, at slow speeds recurrent inhibition in descending V2a neurons supports phasic firing, while bifurcating V2a neurons rely on reciprocal inhibition alone to pattern output. Our findings suggest cell-type-specific, not common, modes of rhythmogenesis generate and coordinate different speeds of locomotion.

Asunto(s)

Larva , Locomoción , Pez Cebra , Animales , Pez Cebra/fisiología , Larva/fisiología , Locomoción/fisiología , Interneuronas/fisiología , Médula Espinal/fisiología , Periodicidad

RESUMEN

Short-term plasticity is an important feature in the brain for shaping neural dynamics and for information processing. Short-term plasticity is known to depend on many factors including brain region, cortical layer, and cell type. Here we focus on vasoactive-intestinal peptide (VIP) interneurons (INs). VIP INs play a key disinhibitory role in cortical circuits by inhibiting other IN types, including Martinotti cells (MCs) and basket cells (BCs). Despite this prominent role, short-term plasticity at synapses to and from VIP INs is not well described. In this study, we therefore characterized the short-term plasticity at inputs and outputs of genetically targeted VIP INs in mouse motor cortex. To explore inhibitory to inhibitory (I → I) short-term plasticity at layer 2/3 (L2/3) VIP IN outputs onto L5 MCs and BCs, we relied on a combination of whole-cell recording, 2-photon microscopy, and optogenetics, which revealed that VIP IN→MC/BC synapses were consistently short-term depressing. To explore excitatory (E) → I short-term plasticity at inputs to VIP INs, we used extracellular stimulation. Surprisingly, unlike VIP IN outputs, E → VIP IN synapses exhibited heterogeneous short-term dynamics, which we attributed to the target VIP IN cell rather than the input. Computational modeling furthermore linked the diversity in short-term dynamics at VIP IN inputs to a wide variability in probability of release. Taken together, our findings highlight how short-term plasticity at VIP IN inputs and outputs is specific to synapse type. We propose that the broad diversity in short-term plasticity of VIP IN inputs forms a basis to code for a broad range of contrasting signal dynamics.

RESUMEN

Background: Psychiatric disorders often emerge during late adolescence/early adulthood, a period with increased susceptibility to socioenvironmental factors that coincides with incomplete parvalbumin interneuron (PVI) development. Stress during this period causes functional loss of PVIs in the ventral hippocampus (vHip), which has been associated with dopamine system overdrive. This vulnerability persists until the appearance of perineuronal nets (PNNs) around PVIs. We assessed the long-lasting effects of adolescent or adult stress on behavior, ventral tegmental area dopamine neuron activity, and the number of PVIs and their associated PNNs in the vHip. Additionally, we tested whether PNN removal in the vHip of adult rats, proposed to reset PVIs to a juvenile-like state, would recreate an adolescent-like phenotype of stress susceptibility. Methods: Male rats underwent a 10-day stress protocol during adolescence or adulthood. Three to 4 weeks poststress, we evaluated behaviors related to anxiety, sociability, and cognition, ventral tegmental area dopamine neuron activity, and the number of PV+ and PNN+ cells in the vHip. Furthermore, adult animals received intra-vHip infusion of ChABC (chondroitinase ABC) to degrade PNNs before undergoing stress. Results: Unlike adult stress, adolescent stress induced anxiety responses, reduced sociability, cognitive deficits, ventral tegmental area dopamine system overdrive, and decreased PV+ and PNN+ cells in the vHip. However, intra-vHip ChABC infusion caused the adult stress to produce changes similar to the ones observed after adolescent stress. Conclusions: Our findings underscore adolescence as a period of heightened vulnerability to the long-lasting impact of stress and highlight the protective role of PNNs against stress-induced damage in PVIs.

---

In this work, we aimed to go deeper into understanding perineuronal nets (PNNs), a specialized extracellular matrix that evolves and protects inhibitory neurons in the brain, specifically parvalbumin-positive interneurons (PVIs). PVIs are essential in regulating brain activity. PNNs only reach maturity in adulthood, which leaves these interneurons unprotected during early life. To investigate this vulnerability, we conducted experiments in which we exposed adolescent and adult animals to a stress protocol. We observed that adolescent animals exhibited a higher susceptibility to developing changes associated with psychiatric disorders later in life. This susceptibility may stem from the absence of PNN protection around their PVIs. To explore this possibility further, we administered an enzyme into a specific brain region, the ventral hippocampus, of adult animals to selectively remove PNNs and induce an adolescent-like state. When subjected to stress, these animals displayed abnormalities similar to those observed in animals stressed during adolescence. Our findings have significant implications, suggesting that the presence of PNN protection around PVIs may be critical for mitigating stress-related psychiatric disorders.

RESUMEN

Slow and fast movements are controlled by distinct sets of spinal V2a neurons with matching properties and connections.

Asunto(s)

Neuronas , Animales , Neuronas/fisiología , Movimiento/fisiología , Humanos , Médula Espinal/fisiología

RESUMEN

Alzheimer's disease (AD) is a severe neurodegenerative disorder and the most common form of dementia, causing the loss of cognitive function. Our previous study has shown, using a doubly mutated mouse model of AD (APP/PS1), that the neural adhesion molecule L1 directly binds amyloid peptides and decreases plaque load and gliosis when injected as an adeno-associated virus construct (AAV-L1) into APP/PS1 mice. In this study, we microinjected AAV-L1, using a Hamilton syringe, directly into the 3-month-old APP/PS1 mouse hippocampus and waited for a year until significant neurodegeneration developed. We stereologically counted the principal neurons and parvalbumin-positive interneurons in the hippocampus, estimated the density of inhibitory synapses around principal cells, and compared the AAV-L1 injection models with control injections of green fluorescent protein (AAV-GFP) and the wild-type hippocampus. Our results show that there is a significant loss of granule cells in the dentate gyrus of the APP/PS1 mice, which was improved by AAV-L1 injection, compared with the AAV-GFP controls (p < 0.05). There is also a generalized loss of parvalbumin-positive interneurons in the hippocampus of APP/PS1 mice, which is ameliorated by AAV-L1 injection, compared with the AAV-GFP controls (p < 0.05). Additionally, AAV-L1 injection promotes the survival of inhibitory synapses around the principal cells compared with AAV-GFP controls in all three hippocampal subfields (p < 0.01). Our results indicate that L1 promotes neuronal survival and protects the synapses in an AD mouse model, which could have therapeutic implications.

RESUMEN

GABAergic interneurons (INs) in the mammalian forebrain represent a diverse population of cells that provide specialized forms of local inhibition to regulate neural circuit activity. Over the last few decades, the development of a palette of genetic tools along with the generation of single-cell transcriptomic data has begun to reveal the molecular basis of IN diversity, thereby providing deep insights into how different IN subtypes function in the forebrain. In this review, we outline the emerging picture of cortical and hippocampal IN speciation as defined by transcriptomics and developmental origin and summarize the genetic strategies that have been utilized to target specific IN subtypes, along with the technical considerations inherent to each approach. Collectively, these methods have greatly facilitated our understanding of how IN subtypes regulate forebrain circuitry via cell type and compartment-specific inhibition and thus have illuminated a path toward potential therapeutic interventions for a variety of neurocognitive disorders.

RESUMEN

The cytoarchitecture of the striatum is remarkably homogeneous, in contrast to the regional variation in striatal functions. Whether differences in the intrinsic membrane properties of striatal neurons contribute to regional heterogeneity has not been addressed systematically. We made recordings throughout the young adult mouse striatum under identical conditions, with synaptic input blocked, from four major striatal neuron types, namely, the two subtypes of spiny projection neurons (SPNs), cholinergic interneurons (ChIs), and fast-spiking GABAergic interneurons (FSIs), sampling at least 100 cells per cell type. Regional variation manifested across all cell types. All cell types in the nucleus accumbens (NAc) shell had higher input impedance and increased excitability. Cells in the NAc core were differentiated from the caudate-putamen (CPu) for both SPN subtypes by smaller action potentials and increased excitability. Similarity between the two SPN subtypes showed regional variation, differing more in the NAc than in the CPu. So, in the Str, both the intrinsic properties of interneurons and projection neurons are regionally heterogeneous, with the greatest difference between the NAc and CPu; greater excitability of NAc shell neurons may make the region more susceptible to activity-dependent plasticity.

RESUMEN

Theory predicts that nonlinear summation of synaptic potentials within dendrites allows neurons to perform linearly non-separable computations (LNSCs). Using Boolean analysis approaches, we predicted that both supralinear and sublinear synaptic summation could allow single neurons to implement a type of LNSC, the feature binding problem (FBP), which does not require inhibition contrary to the exclusive-or function (XOR). Notably, sublinear dendritic operations enable LNSCs when scattered synaptic activation generates increased somatic spike output. However, experimental demonstrations of scatter-sensitive neuronal computations have not yet been described. Using glutamate uncaging onto cerebellar molecular layer interneurons, we show that scattered synaptic-like activation of dendrites evoked larger compound EPSPs than clustered synaptic activation, generating a higher output spiking probability. Moreover, we also demonstrate that single interneurons can indeed implement the FBP. Using a biophysical model to explore the conditions in which a neuron might be expected to implement the FBP, we establish that sublinear summation is necessary but not sufficient. Other parameters such as the relative sublinearity, the EPSP size, depolarization amplitude relative to action potential threshold, and voltage fluctuations all influence whether the FBP can be performed. Since sublinear synaptic summation is a property of passive dendrites, we expect that many different neuron types can implement LNSCs.

Asunto(s)

Dendritas , Interneuronas , Modelos Neurológicos , Dendritas/fisiología , Animales , Interneuronas/fisiología , Potenciales de Acción/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Sinapsis/fisiología , Cerebelo/fisiología , Cerebelo/citología , Neuronas/fisiología , Ratones

RESUMEN

Drug addiction is a chronic and relapse brain disorder. Psychostimulants such as cocaine and amphetamine are highly addictive drugs. Abuse drugs target various brain areas in the nervous system. Recent studies have shown that the prefrontal cortex (PFC) plays a key role in regulating addictive behaviors. The PFC is made up of excitatory glutamatergic cells and gamma-aminobutyric acid (GABAergic) interneurons. Recently, studies showed that GABA level was related with psychostimulant addiction. In this review, we will introduce the role and mechanism of GABA and γ-aminobutyric acid receptors (GABARs) of the PFC in regulating drug addiction, especially in psychostimulant addiction.

Asunto(s)

Estimulantes del Sistema Nervioso Central , Corteza Prefrontal , Trastornos Relacionados con Sustancias , Ácido gamma-Aminobutírico , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Humanos , Ácido gamma-Aminobutírico/metabolismo , Animales , Trastornos Relacionados con Sustancias/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Receptores de GABA/metabolismo

RESUMEN

Amyotrophic lateral sclerosis (ALS) consists of a group of adult-onset fatal and incurable neurodegenerative disorders characterized by the progressive death of motor neurons (MNs) throughout the central nervous system (CNS). At first, ALS was considered to be an MN disease, caused by cell-autonomous mechanisms acting specifically in MNs. Accordingly, data from ALS patients and ALS animal models revealed alterations in excitability in multiple neuronal populations, including MNs, which were associated with a variety of cellular perturbations such as protein aggregation, ribonucleic acid (RNA) metabolism defects, calcium dyshomeostasis, modified electrophysiological properties, and autophagy malfunctions. However, experimental evidence rapidly demonstrated the involvement of other types of cells, including glial cells, in the etiopathogenesis of ALS through non-cell autonomous mechanisms. Surprisingly, the contribution of pre-motor interneurons (INs), which regulate MN activity and could therefore critically modulate their excitability at the onset or during the progression of the disease, has to date been severely underestimated. In this article, we review in detail how spinal pre-motor INs are affected in ALS and their possible involvement in the etiopathogenesis of the disease.

RESUMEN

Objective. Transcranial ultrasound (US) stimulation serves as an external input to a neuron, and thus the evoked response relies on neurons' intrinsic properties. Neural activity is limited to a couple hundred hertz and often exhibits preference to input frequencies. Accordingly, US pulsed at specific physiologic pulse repetition frequencies (PRFs) may selectively engage neurons with the corresponding input frequency preference. However, most US parametric studies examine the effects of supraphysiologic PRFs. It remains unclear whether pulsing US at different physiologic PRFs could activate distinct neurons in the awake mammalian brain.Approach. We recorded cellular calcium responses of individual motor cortex neurons to US pulsed at PRFs of 10, 40, and 140 Hz in awake mice. We compared the evoked responses across these PRFs in the same neurons. To further understand the cell-type dependent effects, we categorized the recorded neurons as parvalbumin positive fast spiking interneurons or putative excitatory neurons and analyzed single-cell mechanosensitive channel expression in mice and humans using the Allen Brain Institute's RNA-sequencing databases.Main results. We discovered that many neurons were preferentially activated by only one PRF and different PRFs selectively engaged distinct neuronal populations. US-evoked cellular calcium responses exhibited the same characteristics as those naturally occurring during spiking, suggesting that US increases intrinsic neuronal activity. Furthermore, evoked responses were similar between fast-spiking inhibitory neurons and putative excitatory neurons. Thus, variation in individual neuron's cellular properties dominates US-evoked response heterogeneity, consistent with our observed cell-type independent expression patterns of mechanosensitive channels across individual neurons in mice and humans. Finally, US transiently increased network synchrony without producing prolonged over-synchronization that could be detrimental to neural circuit functions.Significance. These results highlight the feasibility of activating distinct neuronal subgroups by varying PRF and the potential to improve neuromodulation effects by combining physiologic PRFs.

Asunto(s)

Ratones Endogámicos C57BL , Neuronas , Ondas Ultrasónicas , Animales , Ratones , Neuronas/fisiología , Corteza Motora/fisiología , Masculino , Humanos , Femenino

RESUMEN

The maturation of cerebral cortical networks during early life involves a major reorganization of long-range axonal connections. In a recent study, Bragg-Gonzalo, Aguilera, et al. discovered that in mice, the interhemispheric connections sent by S1L4 callosal projection neurons are pruned via the tight control of their ipsilateral synaptic integration, which relies on the early activity of specific interneurons.

Asunto(s)

Corteza Cerebral , Inhibición Neural , Animales , Inhibición Neural/fisiología , Corteza Cerebral/fisiología , Humanos , Neuronas/fisiología , Vías Nerviosas/fisiología , Cuerpo Calloso/fisiología , Interneuronas/fisiología , Red Nerviosa/fisiología , Ratones

RESUMEN

Adverse experiences during infancy and adolescence have an important and enduring effect on the brain and are predisposing factors for mental disorders, particularly major depression. This impact is particularly notable in regions with protracted development, such as the prefrontal cortex. The inhibitory neurons of this cortical region are altered by peripubertal stress (PPS), particularly in female mice. In this study we have explored whether the inhibitory circuits of the thalamus are impacted by PPS in male and female mice. This diencephalic structure, as the prefrontal cortex, also completes its development during postnatal life and is affected by adverse experiences. The long-term changes induced by PPS were exclusively found in adult female mice. We have found that PPS increases depressive-like behavior and induces changes in parvalbumin-expressing (PV+) cells of the thalamic reticular nucleus (TRN). We observed reductions in the volume of the TRN, together with those of parameters related to structures/molecules that regulate the plasticity and connectivity of PV+ cells: perineuronal nets, matricellular structures surrounding PV+ neurons, and the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). The expression of the GluN1, but not of GluN2C, NMDA receptor subunit was augmented in the TRN after PPS. An increase in the fluorescence intensity of PV+ puncta was also observed in the synaptic output of TRN neurons in the lateral posterior thalamic nucleus. These results demonstrate that the inhibitory circuits of the thalamus, as those of the prefrontal cortex, are vulnerable to the effects of aversive experiences during early life, particularly in females. This vulnerability is probably related to the protracted development of the TRN and might contribute to the development of psychiatric disorders.

Asunto(s)

Estrés Psicológico , Animales , Femenino , Masculino , Ratones , Estrés Psicológico/metabolismo , Estrés Psicológico/patología , Núcleos Talámicos/metabolismo , Ratones Endogámicos C57BL , Parvalbúminas/metabolismo , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo

RESUMEN

Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer's disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aß plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aß deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.

Asunto(s)

Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Animales Recién Nacidos , Neuronas Colinérgicas , Ratones Endogámicos C57BL , Ratones Transgénicos , Neocórtex , Animales , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ratones , Neocórtex/metabolismo , Neocórtex/patología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Neuronas Colinérgicas/patología , Neuronas Colinérgicas/metabolismo , Presenilina-1/genética , Hipoxia-Isquemia Encefálica/patología , Hipoxia-Isquemia Encefálica/metabolismo , Hipoxia-Isquemia Encefálica/genética , Lesiones Encefálicas/patología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/genética , Colina O-Acetiltransferasa/metabolismo , Colina O-Acetiltransferasa/genética , Humanos , Masculino , Modelos Animales de Enfermedad

RESUMEN

Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer's disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1ß2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brain's endogenous γ-oscillations through enhancing the function of PV+INs.

Asunto(s)

Enfermedad de Alzheimer , Cognición , Modelos Animales de Enfermedad , Ritmo Gamma , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Ratones , Cognición/efectos de los fármacos , Ritmo Gamma/efectos de los fármacos , Memoria/efectos de los fármacos , Receptores de GABA-A/metabolismo , Ratones Transgénicos , Humanos , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Alanina/análogos & derivados , Azepinas

RESUMEN

Introduction: Dysfunction of the cortico-basal circuitry - including its primary input nucleus, the striatum - contributes to neuropsychiatric disorders, such as autism and Tourette Syndrome (TS). These conditions show marked sex differences, occurring more often in males than in females. Regulatory interneurons, such as cholinergic interneurons (CINs) and parvalbumin-expressing GABAergic fast spiking interneurons (FSIs), are implicated in human neuropsychiatric disorders such as TS, and ablation of these interneurons produces relevant behavioral pathology in male mice, but not in females. Here we investigate sex differences in the density and distribution of striatal interneurons. Methods: We use stereological quantification of CINs, FSIs, and somatostatin-expressing (SOM) GABAergic interneurons in the dorsal striatum (caudate-putamen) and the ventral striatum (nucleus accumbens) in male and female mice. Results: Males have a higher density of CINs than females, especially in the dorsal striatum; females have equal distribution between dorsal and ventral striatum. FSIs showed similar distributions, with a greater dorsal-ventral density gradient in males than in females. SOM interneurons were denser in the ventral than in the dorsal striatum, with no sex differences. Discussion: These sex differences in the density and distribution of FSIs and CINs may contribute to sex differences in basal ganglia function, particularly in the context of psychopathology.