Higher body mass index predicts cardiac autonomic dysfunction: A longitudinal study in adolescent type 1 diabetes.

BACKGROUND: Obesity is associated with an increased risk of cardiovascular morbidity in adults with diabetes. OBJECTIVE: To examine the predictive role of body mass index (BMI) and adiposity on cardiac autonomic function in childhood onset type 1 diabetes. SUBJECTS: Two hundred and fifty-three participants with type 1 diabetes (aged 8-30 years) were assessed for diabetes complications at a tertiary hospital, and followed over 7 years (total 922 visits). METHODS: Heart rate variability (HRV) measures assessed by 10-minute electrocardiography recording using LabChart Pro were standard deviation of RR intervals, time between consecutive QRS complexes, [SDNN], root mean squared difference of successive RR intervals (RMSSD), triangular index (TI), and low to high frequency ratio [LF:HF]. Multivariable generalized estimating equations were used to model the longitudinal associations between HRV measures and clinical variables (BMI standard deviation scores [SDS], waist:height ratio, total daily insulin dose/kg (TDD) and hemoglobin A1c [HbA1c]). RESULTS: At baseline, mean age was 14.4 ± 2.7 years, diabetes duration 7.1 ± 3.7 years, HbA1c 8.3% ± 1.5% (67 ± 16 mmol/mol), and 33% were overweight/obese (BMI ≥85th percentile). At final visit, mean age was 18.5 ± 2.7 years, duration 11.3 ± 3.9 years, HbA1c 9.0% ± 1.8% (75 ± 20 mmol/mol), and 40% were overweight/obese. Adiposity (higher BMI SDS or waist: height ratio) was a significant predictor of worse HRV (lower SDNN, RMSSD; P < .05), while higher HbA1c and TDD predicted all adverse HRV measures (lower SDNN, RMSSD, TI; P < .05) and abnormal sympathovagal balance (higher LF:HF ratio; P < .05). CONCLUSIONS: Higher BMI and central adiposity are associated with cardiac autonomic dysfunction in childhood onset type 1 diabetes, after adjusting for HbA1c. Interventions targeting overweight/obesity during adolescence may optimize long-term vascular health in type 1 diabetes.

Sustained Gq-Protein Signaling Disrupts Striatal Circuits via JNK.

The dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. The functionality of striatal neurons is tightly controlled by various metabotropic receptors. Whereas the Gs/Gi-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of Gq-protein-dependent signals remain poorly understood. Here, using different experimental approaches, especially designer receptor exclusively activated by designer drug (DREADD) chemogenetic technology, we found that sustained activation of Gq-protein signaling impairs the functionality of striatal neurons and we unveil the precise molecular mechanism underlying this process: a phospholipase C/Ca2+/proline-rich tyrosine kinase 2/cJun N-terminal kinase pathway. Moreover, engagement of this intracellular signaling route was functionally active in the mouse dorsal striatum in vivo, as proven by the disruption of neuronal integrity and behavioral tasks. To analyze this effect anatomically, we manipulated Gq-protein-dependent signaling selectively in neurons belonging to the direct or indirect striatal pathway. Acute Gq-protein activation in direct-pathway or indirect-pathway neurons produced an enhancement or a decrease, respectively, of activity-dependent parameters. In contrast, sustained Gq-protein activation impaired the functionality of direct-pathway and indirect-pathway neurons and disrupted the behavioral performance and electroencephalography-related activity tasks controlled by either anatomical framework. Collectively, these findings define the molecular mechanism and functional relevance of Gq-protein-driven signals in striatal circuits under normal and overactivated states. SIGNIFICANCE STATEMENT: The dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. Whereas the Gs/Gi-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of Gq-protein-dependent signals remain unclear. Here, we show that striatal circuits can be "turned on" by acute Gq-protein signaling or "turned off" by sustained Gq-protein signaling. Specifically, sustained Gq-protein signaling inactivates striatal neurons by an intracellular pathway that relies on cJun N-terminal kinase. Overall, this study sheds new light onto the molecular mechanism and functional relevance of Gq-protein-driven signals in striatal circuits under normal and overactivated states.

Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease.

In hereditary neurodegenerative Huntington disease (HD), early cognitive impairments before motor deficits have been hypothesized to result from dysfunction in the striatum and cortex before degeneration. To test this hypothesis, we examined the firing properties of single cells and local field activity in the striatum and cortex of pre-motor-symptomatic R6/1 transgenic mice while they were engaged in a procedural learning task, the performance on which typically depends on the integrity of striatum and basal ganglia. Here, we report that a dramatically diminished recruitment of the vulnerable striatal projection cells, but not local interneurons, of R6/1 mice in coding for the task, compared with WT littermates, is associated with severe deficits in procedural learning. In addition, both the striatum and cortex in these mice showed a unique oscillation at high γ-frequency. These data provide crucial information on the in vivo cellular processes in the corticostriatal pathway through which the HD mutation exerts its effects on cognitive abilities in early HD.

"Ectopic" theta oscillations and interictal activity during slow-wave state in the R6/1 mouse model of Huntington's disease.

The pathophysiology of Huntington's disease (HD) is primarily associated with striatal degeneration and a number of behavioral symptoms such as involuntary movements, cognitive decline, psychiatric disorders, and in the most juvenile-onset cases with epilepsy. In addition to several changes in cellular and synaptic properties previously reported in HD, attention was recently driven towards the potential relationships between cognitive deficits and sleep disturbances in patients and animal models of Huntington's disease. In the present study, we have investigated whether the population-activity patterns normally expressed by the hippocampal and neocortical circuits during active and slow-wave states are affected in R6/1 mice, a model of Huntington's disease. By performing electrophysiological recordings from the hippocampus and neocortex of R6/1 mice that were either freely moving, head restrained or anesthetized, we observed an altered segregation of active and slow wave brain states, in relation with an epileptic phenotype. Slow-wave state (SWS) in R6/1 was characterized by the intrusion of active-state features (increased 6-10 Hz theta power and depressed 2-3 Hz delta power) and transient, temporally misplaced ("ectopic") theta oscillations. The epileptic phenotype, in addition to previously reported occasional ictal seizures, was characterized by the systematic presence of interictal activity, confined to SWS. Ectopic theta episodes, which could be reversed by the cholinergic antagonist atropine, concentrated interictal spikes and phase-locked hippocampal sharp-wave-ripples. These results point to major alterations of neuronal activity during rest in R6/1 mice, potentially involving anomalous activation of the cholinergic system, which may contribute to the cognitive deficits observed in Huntington's disease.

Evolution of hippocampal spatial representation over time in mice.

To investigate the intriguing and paradoxical contrast between the time-limited role of the hippocampus in memory consolidation and its permanent contribution to spatial memory as revealed by place cell activity, we carefully monitored the temporal evolution of the same set of place cells in normal naïve mice throughout their familiarization to a spatial context and their consolidation of memory about space. Over six daily recording sessions, despite their widely reported stability, we observed gradual changes in hippocampal place fields and cell firing patterns. These changes were interpreted in terms of both improvement and impoverishment of spatial codes: improvement due to intrinsic place cell plasticity, and impoverishment as a consequence of attentional filtering of allocentric spatial information reaching the hippocampus due to the procedural behavioral requirements of the task, or to hippocampal disengagement as learning progresses.

Kainate receptors act as conditional amplifiers of spike transmission at hippocampal mossy fiber synapses.

Hippocampal mossy fiber (Mf) synapses are viewed as conditional detonators, assisting CA3 cells in complex network functions. By analyzing mice deficient for GluK2 (GluR6), GluK3 (GluR7) and GluK5 (KA2) genes we show that kainate receptors (KARs) play a crucial role in the control of synaptic integration and spike transmission efficacy at Mf synapses. We dissected out the role of the different KAR functions at Mf synapses and we show that presynaptic and postsynaptic KARs concur to amplify unitary Mf synaptic inputs to trigger spike discharge within a wide range of frequencies (from 1 to 50 Hz). Moreover, KARs strongly favor spike transmission in response to patterns of presynaptic activity mimicking in vivo dentate granule cell activity. By amplifying spike transmission, KARs also facilitate the induction of associative long-term potentiation in CA3. Hence the actions of KARs as amplifiers of spike transmission contribute largely to the "conditional detonator" function of Mf synapses and are likely important for spatial information processing.

Differential involvement of prefrontal cortex, striatum, and hippocampus in DRL performance in mice.

Behavioral effects of neurotoxic lesions of the hippocampus, medial prefrontal (prelimbic, infralimbic and anterior cingulate) cortex or dorsal striatum were assessed using a DRL-10s schedule in mice. Post-operative acquisition data indicate that mice with hippocampal, but not prefrontal or striatal lesions received fewer reinforcements during daily 30-min sessions, and were less efficient in the timing of their responses. Additional analysis of inter-response-time (IRT) distributions revealed that the responses of hippocampal-lesioned mice exhibited undistinguishable responses for short IRTs (up to 9s). In addition, prefrontal-lesioned mice demonstrated a degradation of performance with further testing, and a flattened IRT distribution at late test phase, while striatal-lesioned mice behaved similarly to sham-lesioned mice. These results are interpreted in terms of known functions of the hippocampus in behavioral inhibition, and of the prefrontal cortex in executive control/decision making (and time production).

Correlations Between Mutant Huntingtin Aggregates and Behavioral Changes in R6/1 Mice.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of the trinucleotide CAG in the HD gene. While the presence of nuclear aggregates of mutant huntingtin (mHtt) in neurons is a hallmark of HD, the reason behind its toxicity remains elusive. OBJECTIVE: The present study was conducted to assess a correlation between the number of mHtt aggregates and the severity of HD symptoms in R6/1 mice. METHODS: We investigated correlations between behavioral deficits and the level of nuclear mHtt aggregates in different neuroanatomical regions in 3-month-old R6/1 mice, the age at which a large variability of symptom severity between animals has been observed. RESULTS: R6/1 mice were deficient in instinctive and anxiety related behaviors as well as long-term memory capabilities. Significant differences were also found between the sexes; female transgenic mice displayed less severe deficits than males. While the level of mHtt aggregates was correlated with the severity of HD phenotypes in most regions of interest, an opposite relationship also was found for some other regions examined. CONCLUSIONS: The obtained results suggest harmful and region-specific roles of mHtt aggregates in HD symptoms.

Neurophysiological and Behavioral Effects of Anti-Orexinergic Treatments in a Mouse Model of Huntington's Disease.

Huntington's disease (HD) is associated with sleep and circadian disturbances in addition to hallmark motor and cognitive impairments. Electrophysiological studies on HD mouse models have revealed an aberrant oscillatory activity at the beta frequency, during sleep, that is associated with HD pathology. Moreover, HD animal models display an abnormal sleep-wake cycle and sleep fragmentation. In this study, we investigated a potential involvement of the orexinergic system dysfunctioning in sleep-wake and circadian disturbances and abnormal network (i.e., beta) activity in the R6/1 mouse model. We found that the age at which orexin activity starts to deviate from normal activity pattern coincides with that of sleep disturbances as well as the beta activity. We also found that acute administration of Suvorexant, an orexin 1 and orexin 2 receptor antagonist, was sufficient to decrease the beta power significantly and to improve sleep in R6/1 mice. In addition, a 5-day treatment paradigm alleviated cognitive deficits and induced a gain of body weight in female HD mice. These results suggest that restoring normal activity of the orexinergic system could be an efficient therapeutic solution for sleep and behavioral disturbances in HD.

Early neurochemical modifications of monoaminergic systems in the R6/1 mouse model of Huntington's disease.

Huntington's disease (HD) is a rare, autosomal neurodegenerative disease characterized by motor and cognitive impairments appearing in adults. The R6/1 mouse model of the disease recapitulates the adult onset of motor symptoms preceded by cognitive and affective deficits. The monoaminergic systems participate in the establishment of motor and cognitive loops and we postulated that their organization and interaction could be precociously altered. Using tissue measurement of dopamine (DA), serotonin (5-HT), noradrenaline, and some metabolites, we observed that DA and/or its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), but not 5-HT or noradrenaline tissue content was reduced in an age-dependent manner (from two to six months) in the striatum, substantia nigra and globus pallidus of R6/1 mice. The metabolite of 5-HT was also lower in R6/1 mice, mainly in the substantia nigra and hippocampus. We then addressed early disorganization of monoaminergic systems in 18 brain regions encompassing several neurobiological networks in 35 day-old animals. DA tissue content was not altered in the striatum or substantia nigra but was decreased in the nucleus accumbens and increased in the globus pallidus. The correlations of monoaminergic index in-between the 18 selected brain regions revealed distinct organizations of monoamines in R6/1 mice, notably marked by a loss of the number of correlations of the DOPAC/DA ratio. The neurochemical analyses show that each monoaminergic system is distinctly altered in the R6/1 mouse model. The early abnormal organization of these systems likely points out altered maturation of neurobiological networks at early stages of HD.

Alteration of GABAergic neurotransmission in Huntington's disease.

Hereditary Huntington's disease (HD) is characterized by cell dysfunction and death in the brain, leading to progressive cognitive, psychiatric, and motor impairments. Despite molecular and cellular descriptions of the effects of the HD mutation, no effective pharmacological treatment is yet available. In addition to well-established alterations of glutamatergic and dopaminergic neurotransmitter systems, it is becoming clear that the GABAergic systems are also impaired in HD. GABA is the major inhibitory neurotransmitter in the brain, and GABAergic neurotransmission has been postulated to be modified in many neurological and psychiatric diseases. In addition, GABAergic neurotransmission is the target of many drugs that are in wide clinical use. Here, we summarize data demonstrating the occurrence of alterations of GABAergic markers in the brain of HD carriers as well as in rodent models of the disease. In particular, we pinpoint HD-related changes in the expression of GABAA receptors (GABAA Rs). On the basis that a novel GABA pharmacology of GABAA Rs established with more selective drugs is emerging, we argue that clinical treatments acting specifically on GABAergic neurotransmission may be an appropriate strategy for improving symptoms linked to the HD mutation.

A new test for long-term spatial memory using an operant chamber in mice.

As part of ongoing efforts to develop fully automated and standardized behavioral tasks to probe cognitive and mnemonic capabilities of mice, we have constructed a new rectangular operant chamber. The chamber contains numerous nose poke holes, distributed over three of its inner walls that are identifiable by their spatial locations. Using this apparatus, we have developed a 'spatial' memory task using a successive reversal discrimination paradigm. Mice learn to discriminate, by trial and error, the position of a single valid hole during a Presentation session wherein they obtained a maximum of 20 reinforcements or 15 min time elapsed. Following a delay interval, they were resubmitted to the same task (Test) using the same reinforced hole. Results indicated that C57BL/6 mice exhibited a significant improvement during the Test, the magnitude of the improvement (memory savings) being dependent on the length of retention intervals ranging from 5 min to 24h. In addition, discrimination performance was sensitive to scopolamine in a dose dependent manner. The simplicity in task set up and the minimal labor and space requirements make this task suitable for high throughput behavioral characterization of genetically modified mice.

A long list visuo-spatial sequential learning in mice.

Sequential learning has been extensively studied in humans using the serial reaction time (SRT) paradigm, and has contributed significantly to the description of the neurobiological processes and substrates underlying different memory systems. More precisely, patients with basal ganglia, but not medial temporal lobe pathology exhibit selective deficits in this task, qualified as implicit learning, since this learning occurs without any conscious awareness of the subjects. While, the construction of transgenic mouse models of human neurological diseases has created a great need for developing mouse analogs of this or other types of human memory tasks, only a few studies exist in rodents, and more specifically in mice. The present study is aimed at examining a SRT protocol for mice using our new operant chamber designed to be polyvalent for different experimental conditions and uses. We provide data for learning by normal C57BL/6 mice of a repeating sequence of 12 nose poke responses, first, via the observation of increases in reaction times when repeated sequence is replaced by random sequence, and, second, by analysis of behavior during transfer trials in which one sequential element is discretely replaced by a new item. The potential of our protocol for dissecting the different neural systems of learning and memory is discussed as well as its usefulness for the validation of transgenic mouse models of human neurodegenerative diseases such as Huntington's disease and Alzheimer's disease.

Changes in striatal activity and functional connectivity in a mouse model of Huntington's disease.

Hereditary Huntington's disease (HD) is associated with progressive motor, cognitive and psychiatric symptoms. A primary consequence of the HD mutation is the preferential loss of medium spiny projection cells with relative sparing of local interneurons in the striatum. In addition, among GABAergic striatal projection cells, indirect pathway cells expressing D2 dopamine receptors are lost earlier than direct pathway cells expressing D1 receptors. To test in vivo the functional integrity of direct and indirect pathways as well as interneurons in the striatum of male R6/1 transgenic mice, we assessed their c-Fos expression levels induced by a striatal-dependent cognitive task and compared them with age-matched wild-type littermates. We found a significant increase of c-Fos+ nuclei in the dorsomedial striatum, and this only at 2 months, when our HD mouse model is still pre-motor symptomatic, the increase disappearing with symptom manifestation. Contrary to our expectation, the indirect pathway projection neurons did not undergo any severer changes of c-Fos expression regardless of age in R6/1 mice. We also found a decreased activation of interneurons that express parvalbumin in the dorsomedial striatum at both presymptomatic and symptomatic ages. Finally, analysis of c-Fos expression in extended brain regions involved in the cognitive learning used in our study, demonstrates, throughout ages studied, changes in the functional connectivity between regions in the transgenic mice. Further analysis of the cellular and molecular changes underlying the transient striatal hyperactivity in the HD mice may help to understand the mechanisms involved in the disease onset.

Differential Alteration in Expression of Striatal GABAAR Subunits in Mouse Models of Huntington's Disease.

Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive motor symptoms that are preceded by cognitive deficits and is considered as a disorder that primarily affects forebrain striatal neurons. To gain a better understanding of the molecular and cellular mechanisms associated with disease progression, we analyzed the expression of proteins involved in GABAergic neurotransmission in the striatum of the R6/1 transgenic mouse model. Western blot, quantitative PCR and immunohistochemical analyses were conducted on male R6/1 mice and age-matched wild type littermates. Analyses were performed on 2 and 6 month-old animals, respectively, before and after the onset of motor symptoms. Expression of GAD 67, GAD 65, NL2, or gephyrin proteins, involved in GABA synthesis or synapse formation did not display major changes. In contrast, expression of α1, α3 and α5 GABAAR subunits was increased while the expression of δ was decreased, suggesting a change in tonic- and phasic inhibitory transmission. Western blot analysis of the striatum from 8 month-old Hdh Q111, a knock-in mouse model of HD with mild deficits, confirmed the α1 subunit increased expression. From immunohistochemical analyses, we also found that α1 subunit expression is increased in medium-sized spiny projection neurons (MSN) and decreased in parvalbumin (PV)-expressing interneurons at 2 and 6 months in R6/1 mice. Moreover, α2 subunit labeling on the PV and MSN cell membranes was increased at 2 months and decreased at 6 months. Alteration of gene expression in the striatum and modification of GABAA receptor subtypes in both interneurons and projection neurons suggested that HD mutation has a profound effect on synaptic plasticity at an early stage, before the onset of motor symptoms. These results also indicate that cognitive and other behavioral deficits may be associated with changes in GABAergic neurotransmission that consequently could be a relevant target for early therapeutic treatment.

Presenilin 1 mutation decreases both calcium and contractile responses in cerebral arteries.

Mutations or upregulation in presenilin 1 (PS1) gene are found in familial early-onset Alzheimer's disease or sporadic late-onset Alzheimer's disease, respectively. PS1 has been essentially studied in neurons and its mutation was shown to alter intracellular calcium (Ca2+) signals. Here, we showed that PS1 is expressed in smooth muscle cells (SMCs) of mouse cerebral arteries, and we assessed the effects of the deletion of exon 9 of PS1 (PS1dE9) on Ca2+ signals and contractile responses of vascular SMC. Agonist-induced contraction of cerebral vessels was significantly decreased in PS1dE9 both in vivo and ex vivo. Spontaneous activity of Ca2+ sparks through ryanodine-sensitive channels (RyR) was unchanged, whereas the RyR-mediated Ca2+-release activated by caffeine was shorter in PS1dE9 SMC when compared with control. Moreover, PS1dE9 mutation decreased the caffeine-activated capacitive Ca2+ entry, and inhibitors of SERCA pumps reversed the effects of PS1dE9 on Ca2+ signals. PS1dE9 mutation also leads to the increased expression of SERCA3, phospholamban, and RyR3. These results show that PS1 plays a crucial role in the cerebrovascular system and the vascular reactivity is decreased through altered Ca2+ signals in PS1dE9 mutant mice.

Omics analysis of mouse brain models of human diseases.

The identification of common gene/protein profiles related to brain alterations, if they exist, may indicate the convergence of the pathogenic mechanisms driving brain disorders. Six genetically engineered mouse lines modelling neurodegenerative diseases and neuropsychiatric disorders were considered. Omics approaches, including transcriptomic and proteomic methods, were used. The gene/protein lists were used for inter-disease comparisons and further functional and network investigations. When the inter-disease comparison was performed using the gene symbol identifiers, the number of genes/proteins involved in multiple diseases decreased rapidly. Thus, no genes/proteins were shared by all 6 mouse models. Only one gene/protein (Gfap) was shared among 4 disorders, providing strong evidence that a common molecular signature does not exist among brain diseases. The inter-disease comparison of functional processes showed the involvement of a few major biological processes indicating that brain diseases of diverse aetiologies might utilize common biological pathways in the nervous system, without necessarily involving similar molecules.

Item organization in three-dimensional space and their discriminability in a mouse operant behavioral task.

In order to study spatial cognition as well as operant/instrumental conditioning or attention processes in the same experimental context in mice, we have designed and constructed an operant chamber that contains a large number of nose poke holes distributed over its inner walls. The nose poke holes were placed three in a horizontal row on one left wall, five in a form of an X on the front wall, and three in a vertical column on one right wall in a hexagonal shaped chamber. This organization of nose poke holes was intended to provide mice with spatially structured environmental cues. Here, we report on an experiment in which providing additional structuring to the standard condition, favoring either further spatial grouping or perceptual/visual clustering of subsets of holes, tremendously facilitated nose poke discrimination learning in normal C57BL/6 mice. More interestingly, mice were able to use their (spatial or mental) representation of holes organization elaborated under spatially or visually structured environment, to improve their learning of a new discrimination under the standard less-structured environment. These findings support the idea that mice are sensitive to subtle visual background information, in addition to spatial information, to organize nose poke items, process similar to both pattern separation and chunking process, in order to minimize interference and to increase items discriminability and their capacity for (long-term) memory.

Early GABAergic transmission defects in the external globus pallidus and rest/activity rhythm alteration in a mouse model of Huntington's disease.

Huntington's disease (HD) is characterized by progressive motor symptoms preceded by cognitive deficits and is regarded as a disorder that primarily affects the basal ganglia. The external globus pallidus (GPe) has a central role in the basal ganglia, projects directly to the cortex, and is majorly modulated by GABA. To gain a better understanding of the time course of HD progression and gain insight into the underlying mechanisms, we analyzed GABAergic neurotransmission in the GPe of the R6/1 mouse model at purportedly asymptomatic and symptomatic stages (i.e., 2 and 6months). Western blot and quantitative polymerase chain reaction (PCR) analyses revealed alterations in the GPe of male R6/1 mice compared with wild-type littermates. Expression of proteins involved in pre- and post-synaptic GABAergic compartments as well as synapse number were severely decreased at 2 and 6months. At both ages, patch-clamp electrophysiological recordings showed a decrease of spontaneous and miniature inhibitory post-synaptic currents (IPSCs) suggesting that HD mutation has an early effect on the GABA signaling in the brain. Therefore, we performed continuous locomotor activity recordings from 2 to 4months of age. Actigraphy analyses revealed rest/activity fragmentation alterations that parallel GABAergic system impairment at 2months, while the locomotor deficit is evident only at 3months in R6/1 mice. Our results reveal early deficits in HD and support growing evidence for a critical role played by the GPe in physiological and pathophysiological states. We suggest that actimetry may be used as a non-invasive tool to monitor early disease progression.

Sleep Physiology Alterations Precede Plethoric Phenotypic Changes in R6/1 Huntington's Disease Mice.

In hereditary neurodegenerative Huntington's disease (HD), there exists a growing consideration that sleep and circadian dysregulations may be important symptoms. It is not known, however, whether sleep abnormalities contribute to other behavioral deficits in HD patients and mouse models. To determine the precise chronology for sleep physiology alterations and other sensory, motor, psychiatric and cognitive symptoms of HD, the same R6/1 HD transgenics and their wild-type littermates were recorded monthly for sleep electroencephalogram (EEG) together with a wide range of behavioral tests according to a longitudinal plan. We found an early and progressive deterioration of both sleep architecture and EEG brain rhythms in R6/1 mice, which are correlated timely with their spatial working memory impairments. Sleep fragmentation and memory impairments were accompanied by the loss of delta (1-4 Hz) power in the transgenic mice, the magnitude of which increased with age and disease progression. These precocious sleep and cognitive impairments were followed by deficits in social behavior, sensory and motor abilities. Our data confirm the existence and importance of sleep physiology alterations in the widely used R6/1 mouse line and highlight their precedence over other plethoric phenotypic changes. The brainwave abnormalities, may represent a novel biomarker and point to innovative therapeutic interventions against HD.