Neuroscience

Thalamocortical (TC) neurons within the ventrolateral thalamus (VL) receive projections from the cerebellum and the basal ganglia (BG) to facilitate motor and non-motor functions. Tonic and rebound firing patterns in response to excitatory cerebellar and inhibitory BG inputs, respectively, are a canonical feature of TC neurons and plays a key role in signal processing. The intrinsic excitability of TC neurons has a strong influence on how they respond to synaptic inputs, however, it is unknown whether their afferents influence their firing properties. Understanding the input-specific firing patterns could shed light into movement disorders with cerebellar or BG involvement. Here, we used whole-cell electrophysiology in brain slices from C57BL/6 mice to investigate the firing of TC neurons with optogenetic confirmation of cerebellar or BG afferents. TC neurons with cerebellar afferents exhibited higher tonic and rebound firing rates than those with BG afferents. This increased firing was associated with faster action potential depolarization kinetics and a smaller afterhyperpolarization potential. We also found differences in the passive membrane properties and sag currents during hyperpolarization. Despite higher rebound firing in TC neurons with cerebellar afferents, there were no differences in T-type calcium channel function compared to those with BG inputs. These data suggest input-specific differences in sodium and SK, but not T-type calcium channels, impact firing properties in TC populations. Altogether, we showed that the pronounced divergence observed in TC neuron firing properties correlate with its heterogeneous anatomical connectivity, which could signify a distinct signal integration and processing by these neurons.

Corticostrial or cortico-basal ganglia circuitry plays an important role in integrating sensory and motor information, developing appropriate goal-directed behavior, promoting the maturation of GABAergic interneurons in the striatum, and regulating the nigrostriatal pathways. Dysfunction of this circuitry has been seen in some movement disorders. However, the dynamic changes of this circuitry in early life are not fully elucidated. Previous studies demonstrated that projections from motor cortices of caudal forelimb and jaw-lip-tongue areas to the striatum developed postnatally with terminal-like fibers evident at postnatal day 7. Here we report the development of the projections from the motor cortex governing whisker and neck movements to the striatum. Corticostriatal projections from this area were mainly ipsilateral and also underwent a progressive, postnatal development. The pyramidal tract and its collaterals to the dorsal striatum appeared on the day of birth (postanatal day 0 (P0)), peaked on P6 in density, and continued to be tuned until P36. The intertelencephalic projections in the dorsolateral striatum were established between P6 and P12 and continued to be refined between P20 and P36. Neurons in this motor cortex sent their axons to the contralateral motor cortex via the corpus callosum at the age between P6 and P12. Our results suggest that the time window between P6 and P12 is critical for the development of the projections from the motor cortex governing whisker and neck movement to the striatum in the rat. The overall process of the development of this circuitry appears to correspond to the functional development of whisker movement and locomotor activities.

A collection of glutamatergic and GABAergic proteins participate in regulating experience-dependent plasticity in the visual cortex (V1). Many studies have characterized changes to those proteins caused by monocular deprivation (MD) during the critical period (CP), but less is known about changes that occur when MD stops. We measured the effects of 3 types of visual experience after MD (n=24, 10 male and 14 female); reverse occlusion (RO), binocular deprivation (BD), or binocular vision, on the expression of synaptic proteins in V1 including glutamatergic and GABAergic receptor subunits. Synapsin expression was increased by RO but not affected by the other treatments. BD shifted the balance between glutamatergic and GABAergic receptor subunits to favor GABAA1. In contrast, BV shifted expression to favor the glutamatergic mechanisms by increasing NMDAR and decreasing GABAA1 subunits. None of the conditions returned normal expression levels to all of the proteins, but BV was the closest.

BackgroundCannabidiol (CBD), one of the main cannabinoids present in the female flowers of Cannabis sativa, has been a therapeutic alternative for a plurality of disorders. Previous investigation has already provided insights into the CBD molecular mechanism, however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we explore the transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days. MethodsC57BL/6JUnib mice were divided into 4 groups treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned and the hippocampal subregions were laser microdissected for RNA-Seq analysis. Data alignment, quantification and analysis were conducted with the STAR Aligner/DESeq2/clusterProfiler R-package pipeline. ResultsWe found changes in gene expression in CA1 neurons after single and multiple CBD administrations. Furthermore, the enrichment analysis of differentially expressed genes following 7 days of CBD administration indicates a widespread decrease in the expression levels of electron transport chain and ribosome biogenesis transcripts, while chromatin modifications and synapse organization transcripts were increased. ConclusionThis dataset provides a significant contribution toward advancing our comprehension of the mechanisms responsible for CBD effects on hippocampal neurons. The findings suggest that CBD prompts a significant reduction in energy metabolism genes and the protein translation machinery in CA1 neurons. SIGNIFICANT OUTCOMESWe identified distinct changes in gene expression of CA1 neurons following both single and multiple administrations of CBD. This highlights the molecular impact of CBD on hippocampal neurons and expands our understanding of its mechanisms of action. We revealed that repeated CBD administration led to a greater number of gene expression alterations compared to a single administration, emphasizing the importance of treatment frequency in modulating gene expression. We found that daily CBD administration for seven days resulted in the downregulation of genes related to energy metabolism and protein synthesis/degradation, while genes involved in chromatin regulation and synapse organization were upregulated. These specific gene expression changes shed light on potential cellular effects and molecular mechanisms underlying CBDs actions in the hippocampus. LIMITATIONSOne limitation of this study is its reliance on animal models, specifically C57BL/6JUnib mice, which may not fully reflect human responses to CBD. Additionally, the study primarily investigated the effects of CBD under healthy conditions and did not directly address its therapeutic effects for specific disorders or conditions. Thus, the clinical relevance and applicability of the findings to therapeutic interventions remain to be determined.

Current hypotheses on the mechanisms underlying the development and plasticity of the ocular dominance system through competitive interactions between pathways serving the two eyes strongly suggest the involvement of neurotrophins and their high affinity receptors. In the cat, infusion of the tyrosine kinase B ligand (trkB), neurotrophin-4/5 (NT-4/5), abolishes ocular dominance plasticity that follows monocular deprivation (Gillespie et al., 2000), while tyrosine kinase A and C ligands (trkA and trkC) do not have this effect. One interpretation of this finding is that NT-4/5 causes overgrowth and sprouting of thalamocortical and/or corticocortical terminals, leading to promiscuous neuronal connections which override the experience-dependent fine tuning of connections based on correlated activity. The present study tested whether neurons in cortical regions infused with NT-4/5 showed anatomical changes compatible with this hypothesis. Cats at the peak of the critical period received chronic infusion NT-4/5 into visual cortical areas 17/18 via an osmotic minipump. Visual cortical neurons were labeled in fixed slices using the DiOlistics methods (Gan et al., 2000) and analyzed in confocal microsco-py. Infusion of NT-4/5 induced a significant increase of spine-like processes on primary dendrites and a distinctive sprouting of protuberances from neuronal somata in all layers. The increase of neuronal membrane was paralleled by an increase in density of the presynaptic marker synaptophysin in infused areas, suggesting an increase in the numbers of synapses. A contingent of these newly formed synapses may feed into inhibitory circuits, as suggested by an increase of GAD-65 immunostaining in NT-4/5 affected areas. These anatomical changes are consistent with the physiological changes in such animals, suggesting that excess trkB neurotrophin can stimulate the formation of promiscuous connections during the critical period.

Patients with Autism Spectrum Disorder (ASD) often exhibit disturbances in sleep, metabolism, and immune system. The molecular mechanisms for these clinical features in ASD are currently unknown. We demonstrated that circadian genes in the cells of patients with ASD often are dysregulated compared to controls. The dysregulation of circadian genes was reflected in two different ways: (1) abnormal levels of expression; and (2) a change of gene-gene association pattern in the co-expression network. We also observed a link between abnormal expression of circadian genes in lymphoblastoid cells with sleep phenotypes in patients with ASD. Our results suggest that circadian genes and circadian rhythms might play critical roles in the pathogenesis of ASD.

CAD cells were derived from Cath.a cells, a mouse central nervous system catecholaminergic cell line. Serum-starved CAD cells undergo morphological changes and resemble isolated neurons when observed by microscopy. We carried out an RNAseq transcriptomic analysis to examine differentiated CAD cells for expression signatures related to neuronal functions, identifying [~]1900 transcripts whose expression changed with differentiation. Pathview analysis identified [~]80 KEGG pathway gene sets that were differentially expressed, including upregulation of at least 13 neuron-related pathways. This dataset can be explored more deeply, allowing further investigation into expression changes relevant to studying neuronal functions in this easy-to-culture model system.

Medium spiny neurons (MSN) of the striatum are known for their bistable membrane potential leading to two states: a hyperpolarized down-state and a depolarized up-state. Glutamatergic inputs from the hippocampus play a key role in switching the cell to the up-state. This gating is known to play a key role in regulating when other synaptic inputs, such as from the cortex, should generate action potentials and when they should be considered as noise. Any deviations from this pattern of state transitions indicates abnormal gating that has implications in conditions such as schizophrenia. Although dopamine is reported to modulate ion channels of MSN sub-types - dMSN and iMSN - its influence on the state transition times and up-state dwell times are not yet examined. We address this lacuna using biophysically constrained spiny models of dMSN and iMSN with explicit dopamine receptors. Our findings indicate a significant increase in up-state dwell time for dMSN and a significant decrease for iMSN when the % activation of DA receptors was increased. Additionally, a strong correlation between state transition times and spiking frequencies of MSN sub-types was observed.

Neuron activity in the sensory cortices mainly depends on feedforward thalamic inputs. High-frequency activity of a thalamic input can be temporally integrated by a neuron in the sensory cortex and is likely to induce larger depolarization. However, feedforward inhibition (FFI) and depression of excitatory synaptic transmission in thalamocortical pathways attenuate depolarization induced by the latter part of high-frequency spiking activity and the temporal summation may not be effective. The spiking activity of a thalamic neuron in a specific temporal pattern may circumvent FFI and depression of excitatory synapses. The present study determined the relationship between the temporal pattern of spiking activity of a single thalamic neuron and the degree of cortical activation as well as that between the firing rate of spiking activity of a single thalamic neuron and the degree of cortical activation. Spiking activity of a thalamic neuron was recorded extracellularly from the lateral geniculate nucleus (LGN) in male Long-Evans rats. Degree of cortical activation was assessed by simultaneous recording of local field potential (LFP) from the visual cortex. A specific temporal pattern appearing in three consecutive spikes of an LGN neuron induced larger cortical LFP modulation than high-frequency spiking activity during a short period. These findings indicate that spiking activity of thalamic inputs is integrated by a synaptic mechanism sensitive to an input temporal pattern. Significance StatementSensory cortical activity depends on thalamic inputs. Despite the importance of thalamocortical transmission, how spiking activity of thalamic inputs is integrated by cortical neurons remains unclear. Feedforward inhibition and synaptic depression of excitatory transmission may not allow simple temporal summation of membrane potential induced by consecutive spiking activity of a thalamic neuron. A specific temporal pattern appearing in three consecutive spikes of a thalamic neuron induced larger cortical local field potential modulation than high-frequency spiking activity during a short period. The findings indicate the importance of the temporal pattern of spiking activity of a single thalamic neuron on cortical activation.

Head direction (HD) cells discharge as a function of the animals directional heading and are believed to underlie ones sense of direction. They have been identified in several brain areas, although the signal is thought to be generated across the connections between the lateral mammillary (LMN) and dorsal tegmental nuclei (DTN). Computational models have proposed that a ring-attractor network underlies the mechanisms that generate the signal. These models usually contain separate populations of neurons that encode HD and angular head velocity (AHV). Currently, both cell types have been identified in the LMN and DTN. However, HD attractor models also require cells, referred to as rotation cells, which are sensitive to both parameters conjunctively (HD+AHV). Here we sought to identify such cells in the LMN-DTN network. We identified two distinct types of HD cells. The majority of LMN HD cells ([~]64%) were AHV-independent, responding only to the animals directional heading. However, a second population ([~]36%) was sensitive to both HD and AHV. Both symmetric and asymmetric AHV cell types were found. Similar results were found in the DTN, but with a higher percentage of conjunctive HD+AHV cells (60%). Notably, many HD+AHV conjunctive cells were also sensitive to the animals linear velocity (LV). In contrast, HD cells in the anterodorsal thalamus were rarely sensitive to AHV or LV. These findings demonstrate that the requisite rotation-type HD cell is present in brain areas responsible for generating the HD signal and supports the view that an attractor style network underlies its generation in mammals. Statements and DeclaratioThis manuscript does not represent the official view of the National Institute of Neurological Disorders and Stroke (USA) (NINDS), the National Institutes of Health (USA) (NIH), or any part of the US Federal Government. No official support or endorsement of this article by the NINDS or NIH is intended or should be inferred.

The pedunculopontine tegmental nucleus of the brainstem is important for a wide range of functions, including sensorimotor integration and regulation of locomotion and discrete forelimb movements. Evidence suggests it is structurally disordered as part of the neuropathology of the movement disorder Parkinsons disease. To assess whether neuronal activity is also affected in parkinsonian model animals we used single neuron recordings in free moving rats to determine the effects of acute drug-induced parkinsonism on the firing rate of the neurons. Acute parkinsonian akinesia was associated with reduction in resting firing rate and increased firing regularity, consistent with reduced excitability in this state.

The coordination of various brain regions achieves both volitional and forced motor control, but the role of the primary motor cortex in proficient running motor control remains unclear. This study trained mice to run at high performance (>10,000 rotations per day or >2,700 rotations per hour) using a running wheel, and then assessed the effects of the removal of bilateral cortical areas including the primary motor cortex on volitional and forced running locomotion. The control sham-operated group revealed a quick recovery of volitional running, reaching half of the maximum daily rotation in 3.9 +/-2.6 days (n = 10). In contrast, the cortical injury group took significantly a longer period (7.0 +/-3.3 days, n = 15) to reach half of the maximum volitional daily rotation, but recovered to preoperative levels in about two weeks. Furthermore, even 3 days after surgery to remove cortical regions, the running time on a treadmill moving at 35.3 cm/sec, which is difficult for naive mice to run on, was not significantly different from that in the sham-operated group. These results suggest that the intact primary motor cortex is not necessarily required to execute trained fast-running locomotion, but rather contributes to the spontaneity of running in mice.

The striatum and its dopaminergic input participate in temporal processing and numerous studies provide evidence that interactions between dopamine and acetylcholine are critical for striatal functioning. However, the role of local cholinergic innervation of the striatum in behaviors requiring precise timing has not been specifically investigated. Here, we recorded from presumed striatal cholinergic interneurons, identified as tonically active neurons (TANs), in two male rhesus monkeys performing self-initiated movements after specified learned time intervals have elapsed since a visual cue. We found that 38% of all recorded TANs responded to the cue with a pause in firing and the strength of these responses could be modulated according to the duration of the interval being timed and the accuracy of time estimates. By examining the TAN response to the reward itself and by recording from TANs during a Pavlovian procedure in which no action was required, we found evidence that TAN activity modulation may potentially reflect differences in the animals prediction of reward. Thus, besides their well-known role in predicting and detecting rewarding events, TANs may generate signals related to the processing of time. Our findings suggest a role of the local cholinergic circuitry in the representation of time within the striatum.

BackgroundParkinsons disease (PD) is caused by the progressive loss of dopaminergic cells in substantia nigra pars compacta (SNc). The root cause of this cell loss in PD is still not decisively elucidated. A recent line of thinking traces the cause of PD neurodegeneration to metabolic deficiency. Due to exceptionally high energy demand, SNc neurons exhibit a higher basal metabolic rate and higher oxygen consumption rate, which results in oxidative stress. Recently, we have suggested that the excitotoxic loss of SNc cells might be due to energy deficiency occurring at different levels of neural hierarchy. Levodopa (LDOPA), a precursor of dopamine, which is used as a symptom-relieving treatment for PD, leads to outcomes that are both positive and negative. Several researchers suggested that LDOPA might be harmful to SNc cells due to oxidative stress. The role of LDOPA in the course of PD pathogenesis is still debatable. New MethodWe hypothesize that energy deficiency can lead to LDOPA-induced toxicity (LIT) in two ways: by promoting dopamine-induced oxidative stress and by exacerbating excitotoxicity in SNc. We present a multiscale computational model of SNc-striatum system, which will help us in understanding the mechanism behind neurodegeneration postulated above and provides insights for developing disease-modifying therapeutics. ResultsIt was observed that SNc terminals are more vulnerable to energy deficiency than SNc somas. During LDOPA therapy, it was observed that higher LDOPA dosage results in increased loss of somas and terminals in SNc. It was also observed that co-administration of LDOPA and glutathione (antioxidant) evades LDOPA-induced toxicity in SNc neurons. Comparison with Existing MethodsOur proposed multiscale model of SNc-striatum system is first of its kind, where SNc neuron was modelled at biophysical level, and striatal neurons were modelled at spiking level. ConclusionsWe show that our proposed model was able to capture LDOPA-induced toxicity in SNc, caused by energy deficiency.

Disruption of neural tracts descending from the brain to the spinal cord after brain trauma and stroke causes postural and sensorimotor deficits. We previously showed that unilateral lesion to the sensorimotor cortex in rats with completely transected thoracic spinal cord produced asymmetry in hindlimb posture and withdrawal reflexes. Supraspinal signals to hindlimb muscles may be transmitted through the paravertebral chain of sympathetic ganglia that remain intact after the transection. We here demonstrated that prior transection of the spinal cord at the cervical level that was rostrally to segments with preganglionic sympathetic neurons, did not abolish formation of asymmetry in hindlimb posture and musculo-articular resistance to stretch after unilateral brain injury. Thus not the sympathetic system but humoral signals may mediate the effects of brain injury on the lumbar spinal circuits. The asymmetric responses in rats with transected spinal cords were eliminated by bilateral lumbar dorsal rhizotomy after the left-side brain injury, but resistant to deafferentation after the right-side brain lesion. Two mechanisms, one dependent on and one independent of afferent input may account for asymmetric hindlimb motor responses. Resistance to deafferentation may be due to sustained stretch- and effort-unrelated muscle contractions that is often observed in patients with central lesions. Left-right asymmetry is unusual feature of these mechanisms that both are activated by humoral signals. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/488460v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@14770e6org.highwire.dtl.DTLVardef@1452343org.highwire.dtl.DTLVardef@e1aedorg.highwire.dtl.DTLVardef@9c8ea_HPS_FORMAT_FIGEXP M_FIG C_FIG

The cellular identity of thalamocortical neurons (TCNs), namely their firing properties, dictates brain-wide activity patterns, such as sleep spindles. Transcription factors are critical to the determination of cellular identity. Previously, we discovered that a subset of TCNs express the transcription factor, Shox2, and, in a global Shox2 KO, established that TCNs within the anterior nucleus of the thalamus rely on the expression of Shox2 to regulate key ion channels that are necessary to maintain their firing properties. From this, we hypothesized that Shox2 expression, through the regulation of firing properties of TCNs, is critical for the thalamocortical circuit to generate spindle oscillations. We exploited the somatosensory thalamocortical circuit to investigate this by creating a primary somatosensory thalamus (VB) Shox2 knockdown mouse model. We delivered Cre into the VB of P21 Shox2fl/fl mice using viral infection and compared in vitro, patch-clamp recordings from Shox2+ and Shox2 knockdown TCNs, finding that Shox2 expression is indeed critical to maintain burst and tonic firing properties of VB TCNs. Since Shox2 is important developmentally and firing from TCNs to cortex during development structures the circuit, we performed ultrasound-guided P3 injections at P3 to generate an early-stage, Shox2 VB knockdown, but found no changes in the layer four, barrel map (VB cortical target). Despite this, Shox2 knockdown mice exhibit reduced sleep-spindle EEG density. Further, key behaviors associated with spindles and proper VB thalamic function--memory consolidation and somatosensory perception--are significantly impaired. These results indicate that the impact on spindle function is likely due to cell autonomous changes to TCNs rather than circuit changes, confirming our hypothesis that Shox2 is necessary for normal thalamic spindle function and implicating a potential role for Shox2 in autism and schizophrenia pathologies.

Capacitance of biological membranes is determined by the properties of the lipid portion of the membrane, as well as morphological features of a cell. In neurons, membrane capacitance is a determining factor of synaptic integration, action potential propagation speed and firing frequency due to its direct effect on the membrane time constant. Besides slow changes associated with increased morphological complexity during postnatal maturation, neuron membrane capacity is largely considered a stable, non-regulated constant magnitude. Here we report that in two excitatory neuronal cell types, pyramidal cells of mouse primary visual cortex and granule cells of the hippocampus, the membrane capacitance significantly changes between the start and the end of a daily light cycle. The changes are large, nearly two-fold in magnitude in pyramidal cells, but are not observed in cortical parvalbumin-expressing inhibitory interneurons. We discuss potential functional implications and plausible mechanisms.

The N-methyl-D-aspartate receptor (NMDAr) hypofunction hypothesis suggests that excitatory-inhibitory (E-I) imbalance underlies cognitive deficits associated with neuropsychiatric disorders, such as schizophrenia (SCZ). In this study, we investigated the impact of NMDAr blockade on pyramidal neurons and interneurons in the CA1 region of the hippocampus using in vivo electrophysiological recordings during both spontaneous and exploratory behaviors. Through the administration of MK-801, an NMDAr antagonist, we assessed changes in spike train dynamics, network synchrony, and neuronal modulation by oscillatory activity, with particular emphasis on theta, gamma, and sharp-wave ripple (SWR) oscillations. We found that NMDAr blockade significantly disrupted the E-I balance, leading to altered spike train properties, reduced bursting propensity, and impaired neuronal synchronization. These changes were accompanied by decreased modulation of pyramidal neurons and interneurons by theta and gamma oscillations, as well as diminished recruitment of pyramidal neurons during SWR events. Additionally, the correlation between firing rates and movement speed was reduced, reflecting deficits in spatial coding and memory processing. Moreover, MK-801 administration disrupted place cell stability and spatial information processing. These effects likely contribute to functional disconnection between the hippocampus and other brain regions, such as the prefrontal cortex, and may underlie SCZ-associated cognitive impairments. Our findings provide valuable insights into the cellular and network-level mechanisms affected by NMDAr dysfunction, highlighting the role of oscillatory activity and spike timing in cognitive deficits. This work advances our understanding of how NMDAr hypofunction impacts hippocampal circuits and identifies potential targets for therapeutic interventions aimed at restoring cognitive function in neuropsychiatric disorders.

The granule cell domain of the cochlear nucleus (GCD) receives input from multimodal brain regions including the second cervical spinal ganglion, the spinal trigeminal nucleus, the cuneate nucleus, and the lateral reticular nucleus. Most of the input are in the form of large mossy fibers and small boutons containing round synaptic vesicles and forming asymmetric synapses. A smaller number of inputs arise from the lateral reticular nucleus and the spinal trigeminal nucleus that contain pleomorphic synaptic vesicles implying inhibitory action. This circumstance positions the GCD for integrating polysensory excitatory and inhibitory inputs at the earliest stages of auditory processing, which suggests a role for segregating sound streams. The structural substrate for such a function is naturally elaborate. Mossy fibers from these different origins are large, multilobed endings that form synaptic glomeruli with postsynaptic targets that include granule cells, unipolar brush cells, cartwheel cells, and chestnut cells, which in turn project to principal cells in the dorsal cochlear nucleus (DCN). Numerous synapses contribute to the integration of the different modalities, but the organization of these synapses is still not well understood. We investigated this issue by labelling the presynaptic endings of different somatosensory inputs using biotinylated dextran amine or Phaseolus vulgaris leucoagglutinin, and studying their post-synaptic relationships in the GCD. The anterogradely-labeled endings and associated targets were visualized by light and electron microscopy. Following computer-aided, three-dimensional reconstructions, we found that unipolar brush cells are the main target of the C2 DRG and cuneate nucleus. Mossy fibers from the spinal trigeminal nucleus project to Golgi cells, an inhibitory neuron. In contrast, inhibitory boutons originated from the lateral reticular nucleus. These results reveal that somatosensory integration in the granule cell domain is achieved by distinctive synaptic wiring and specialized chemical signaling.

BackgroundThe present study examined neurocognitive differences between Perinatally HIV (PHIV)-infected-youth and age and gender matched healthy controls. Despite early, long-term anti-viral treatment (ART), significant neurocognitive deficiencies remain for PHIV-infected-youth reaching adulthood compared to controls. MethodsParticipants were assessed with a comprehensive neuropsychological battery. An Overall Neurocognitive Composite Score and a Global Deficit Score (GDS) were created. Sleep, depression, and developmental level of intellectual functioning were also examined. ResultsPHIV-youth performed more poorly than controls in all neurocognitive domains. Very large effect sizes were observed for the Overall Neurocognitive Composite Score and GDS. PHIV-infected-youth appear to be significantly more depressed compared to controls, but there were no differences in amount or type of sleep observed. ConclusionDespite early, long-term anti-viral treatment (ART), neurocognitive deficiencies remain for PHIV-infected-young-adults. The verbal learning domain was significantly impaired with implications for functioning. The PHIV-infected-youth were also depressed and not receiving treatment for depression.