Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that affects men an... more Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies indicate there may be sex differences in disease progression. One of the early symptoms of HD is disruptions in the circadian timing system, but it is currently unknown whether sex is a factor in these alterations. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s) and designing early intervention strategies, we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in circadian behavioral rhythms are detectable in an animal model of the disease. Similar to BACHDmales, BACHD females display circadian disruptions at both 3 and 6 months of age; however, deficits to BACHD female mouse activity levels, rhythm precision, and behavioral fragmentation are either delayed or less severe relative to males. These sex differe...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 7, 2015
Serine palmitoyltransferase (SPT) is a key enzyme in the first step of sphingolipid biosynthesis.... more Serine palmitoyltransferase (SPT) is a key enzyme in the first step of sphingolipid biosynthesis. Mutations in the SPTLC1 gene that encodes for SPT subunits cause hereditary sensory neuropathy type 1. However, little is understood about how mutant SPT regulates mechanisms of sensory neuron and axonal growth. Using transgenic mice overexpressing the C133W SPT mutant, we found that mutant dorsal root ganglia (DRG) during growth in vitro exhibit increased neurite length and branching, coinciding with elevated expression of actin-cross-linking proteins at the neuronal growth cone, namely phosphorylated Ezrin/Radixin/Moesin. In addition, inhibition of SPT was able to reverse the mutant phenotype. Because mutant SPT preferentially uses l-alanine over its canonical substrate l-serine, we also investigated the effects of substrate availability on DRG neurons. Supplementation with l-serine or removal of l-alanine independently restored normal growth patterns in mutant SPTLC1(C133W) DRG. Ther...
Sleep disorders are common in patients with neurogenerative diseases and manifest early in the di... more Sleep disorders are common in patients with neurogenerative diseases and manifest early in the disease process. Among a number of possible mechanisms underlying the sleep disturbances, there is evidence that dysfunction in the circadian system is a contributing factor. Focusing on a mouse model of Huntington’s disease has enabled us to determine that at the onset of symptoms, spontaneous electrical activity of neurons within the central clock is disrupted even though the molecular clockwork is still functional. These findings suggest that the fundamental deficit contributing to disordered sleep is reduced SCN output. The mechanism underlying this deficit is not yet known, but mitochondrial dysfunction and oxidative stress are likely involved. Disruption of circadian output from the SCN would be expected to have wide ranging impact on the body including SCN regulated brain regions and the heart. In fact, there is a great deal of overlap in the non-motor symptoms experienced by HD patients and the consequences of circadian disruption. This raises the possibility that the disordered sleep and circadian function experienced by HD patients may be an integral part of the disease. Furthermore, we speculate that circadian dysfunction may accelerate the pathology underlying HD. If these hypotheses are correct, we should focus on treating circadian misalignment and sleep disruptions early in disease progression.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 7, 2015
Serine palmitoyltransferase (SPT) is a key enzyme in the first step of sphingolipid biosynthesis.... more Serine palmitoyltransferase (SPT) is a key enzyme in the first step of sphingolipid biosynthesis. Mutations in the SPTLC1 gene that encodes for SPT subunits cause hereditary sensory neuropathy type 1. However, little is understood about how mutant SPT regulates mechanisms of sensory neuron and axonal growth. Using transgenic mice overexpressing the C133W SPT mutant, we found that mutant dorsal root ganglia (DRG) during growth in vitro exhibit increased neurite length and branching, coinciding with elevated expression of actin-cross-linking proteins at the neuronal growth cone, namely phosphorylated Ezrin/Radixin/Moesin. In addition, inhibition of SPT was able to reverse the mutant phenotype. Because mutant SPT preferentially uses l-alanine over its canonical substrate l-serine, we also investigated the effects of substrate availability on DRG neurons. Supplementation with l-serine or removal of l-alanine independently restored normal growth patterns in mutant SPTLC1(C133W) DRG. Ther...
The European journal of neuroscience, Jan 17, 2015
The neuropeptide vasoactive intestinal peptide is expressed at high levels in a subset of neurons... more The neuropeptide vasoactive intestinal peptide is expressed at high levels in a subset of neurons in ventral region of the suprachiasmatic nucleus (SCN). While VIP is known to be important for the synchronization of the SCN network, the role of VIP in photic regulation of the circadian system has received less attention. In the present study, we found that the light-evoked increase in electrical activity in vivo was unaltered by the loss of VIP. In the absence of VIP, the ventral SCN still exhibited NMDA-evoked responses in a brain slice preparation although the absolute levels of neural activity before and after treatment were significantly reduced. Next, we used calcium imaging techniques to determine if the loss of VIP altered the calcium influx due to retinohypothalamic tract stimulation. The magnitude of the evoked calcium influx was not reduced in the ventral SCN but did decline in the dorsal SCN regions. We examined the time course of the photic induction of Period1 in the SC...
The female reproductive cycle is gated by the circadian timing system and may be vulnerable to di... more The female reproductive cycle is gated by the circadian timing system and may be vulnerable to disruptions in the circadian system. Prior work suggests that vasoactive intestinal peptide (VIP)-expressing neurons in the suprachiasmatic nucleus (SCN) are one pathway by which the circadian clock can influence the estrous cycle, but the impact of the loss of this peptide on reproduction has not been assessed. In the present study, we first examine the impact of the genetic loss of the neuropeptide VIP on the reproductive success of female mice. Significantly, mutant females produce about half the offspring of their wild-type sisters even when mated to the same males. We also find that VIP-deficient females exhibit a disrupted estrous cycle; that is, ovulation occurs less frequently and results in the release of fewer oocytes compared with controls. Circadian rhythms of wheel-running activity are disrupted in the female mutant mice, as is the spontaneous electrical activity of dorsal SCN...
Sleep disorders are common in patients with neurogenerative diseases and manifest early in the di... more Sleep disorders are common in patients with neurogenerative diseases and manifest early in the disease process. Among a number of possible mechanisms underlying the sleep disturbances, there is evidence that dysfunction in the circadian system is a contributing factor. Focusing on a mouse model of Huntington's disease has enabled us to determine that at the onset of symptoms, spontaneous electrical activity of neurons within the central clock is disrupted even though the molecular clockwork is still functional. These findings suggest that the fundamental deficit contributing to disordered sleep is reduced SCN output. The mechanism underlying this deficit is not yet known, but mitochondrial dysfunction and oxidative stress are likely involved. Disruption of circadian output from the SCN would be expected to have wide ranging impact on the body including SCN regulated brain regions and the heart. In fact, there is a great deal of overlap in the non-motor symptoms experienced by HD...
The ability to generate intrinsic circadian rhythms in electrical activity appears to be a key pr... more The ability to generate intrinsic circadian rhythms in electrical activity appears to be a key property of central pacemaker neurons and one essential to the function of the circadian timing system. Previous work has demonstrated that suprachiasmatic nucleus (SCN) neurons express the fast delayed rectifier (FDR) potassium current and raise questions about the function of this current. Here, we report that mice lacking both Kcnc1 and Kcnc2 genes [double knockout (dKO)] fail to express the Kv3.1 and 3.2 channels in the SCN as well as exhibit a greatly reduced FDR current. SCN neurons from these dKO mice exhibit reduced spontaneous activity during the day as well as reduced NMDA-evoked excitatory responses during the night. Interestingly, the daily rhythm in PER2 expression in the SCN was not altered in the dKO mice, although the photic induction of c-Fos was attenuated. Behaviorally, the dKO mice exhibited extremely disrupted daily rhythms in wheel-running behavior. In a light/dark cycle, some of the dKO mice were arrhythmic, whereas others expressed a diurnal rhythm with low amplitude and significant activity during the day. When placed in constant darkness, the dKO mice exhibited lowamplitude, fragmented rhythms and attenuated light responses. Together, these data are consistent with the hypothesis that the FDR current is critical for the generation of robust circadian rhythms in behavior as well as the synchronization of the circadian system to the photic environment.
Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, heredi... more Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, hereditary sensory, and autonomic neuropathy type I (HSAN1). We previously reported that mice bearing a transgene-expressing mutant SPTLC1 (tgSPTLC1 C133W) show a reduction in SPT activity and hyperpathia at 10 months of age. Now analyzed at a later age, we find these mice develop sensory loss with a distal small fiber neuropathy and peripheral myelinopathy. This phenotype is largely reversed when these mice are crossed with transgenic mice overexpressing wild-type SPTLC1 showing that the mutant SPTLC1 protein is not inherently toxic. Simple loss of SPT activity also cannot account for the HSAN1 phenotype, since heterozygous SPTLC1 knockout mice have reduced SPT activity but are otherwise normal. Rather, the presence of two newly identified, potentially deleterious deoxysphingoid bases in the tgSPTLC1 C133W , but not in the wild-type, double-transgenic tgSPTLC1 WT ϩ C133W or SPTLC1 ϩ/Ϫ mice, suggests that the HSAN1 mutations alter amino acid selectivity of the SPT enzyme such that palmitate is condensed with alanine and glycine, in addition to serine. This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.
Sleep disorders are nearly ubiquitous among patients with Parkinson's disease (PD), and they mani... more Sleep disorders are nearly ubiquitous among patients with Parkinson's disease (PD), and they manifest early in the disease process. While there are a number of possible mechanisms underlying these sleep disturbances, a primary dysfunction of the circadian system should be considered as a contributing factor. Our laboratory's behavioral phenotyping of a well-validated transgenic mouse model of PD reveals that the electrical activity of neurons within the master pacemaker of the circadian system, the suprachiasmatic nuclei (SCN), is already disrupted at the onset of motor symptoms, although the core features of the intrinsic molecular oscillations in the SCN remain functional. Our observations suggest that the fundamental circadian deficit in these mice lies in the signaling output from the SCN, which may be caused by known mechanisms in PD etiology: oxidative stress and mitochondrial disruption. Disruption of the circadian system is expected to have pervasive effects throughout the body and may itself lead to neurological and cardiovascular disorders. In fact, there is much overlap in the non-motor symptoms experienced by PD patients and in the consequences of circadian disruption. This raises the possibility that the sleep and circadian dysfunction experienced by PD patients may not merely be a subsidiary of the motor symptoms, but an integral part of the disease. Furthermore, we speculate that circadian dysfunction can even accelerate the pathology underlying PD. If these hypotheses are correct, more aggressive treatment of the circadian misalignment and sleep disruptions in PD patients early in the pathogenesis of the disease may be powerful positive modulators of disease progression and patient quality of life.
Many patients with Huntington's disease (HD) exhibit disturbances in their daily cycle of sleep a... more Many patients with Huntington's disease (HD) exhibit disturbances in their daily cycle of sleep and wake as part of their symptoms. These patients have difficulty sleeping at night and staying awake during the day, which has a profound impact on the quality of life of the patients and their care-givers. In the present study, we examined diurnal and circadian rhythms of four models of HD including the BACHD, CAG 140 knock-in and R6/2 CAG 140 and R6/2 CAG 250 lines of mice. The BACHD and both R6/2 lines showed profound circadian phenotypes as measured by wheel-running activity. Focusing on the BACHD line for further analysis, the amplitude of the rhythms in the BACHD mice declined progressively with age. In addition, the circadian regulation of heart rate and body temperature in freely behaving BACHD mice were also disrupted. Furthermore, the distribution of sleep as well as the autonomic regulation of heart rate was disrupted in this HD model. To better understand the mechanistic underpinnings of the circadian disruption, we used electrophysiological tools to record from neurons within the central clock in the suprachiasmatic nucleus (SCN). The BACHD mice exhibit reduced rhythms in spontaneous electrical activity in SCN neurons. Interestingly, the expression of the clock gene PERIOD2 was not altered in the SCN of the BACHD line. Together, this data is consistent with the hypothesis that the HD mutations interfere with the expression of robust circadian rhythms in behavior and physiology. The data raise the possibility that the electrical activity within the central clock itself may be altered in this disease.
Compelling reasons to study the role of sex in the circadian system include the higher rates of s... more Compelling reasons to study the role of sex in the circadian system include the higher rates of sleep disorders in women than in men and evidence that sex steroids modulate circadian control of locomotor activity. To address the issue of sex differences in the circadian system, we examined daily and circadian rhythms in wheel-running activity, electrical activity within the suprachiasmatic nucleus, and PER2::LUC-driven bioluminescence of gonadally-intact adult male and female C57BL/6J mice. We observed greater precision of activity onset in 12-hour light, 12-hour dark cycle for male mice, longer activity duration in 24 hours of constant darkness for female mice, and phase-delayed PER2::LUC bioluminescence rhythm in female pituitary and liver. Next, in order to investigate whether sex differences in behavior are sex chromosome or gonadal sex dependent, we used the 4 core genotypes (FCG) mouse model, in which sex chromosome complement is independent of gonadal phenotype. Gonadal males...
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that affects men an... more Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies indicate there may be sex differences in disease progression. One of the early symptoms of HD is disruptions in the circadian timing system, but it is currently unknown whether sex is a factor in these alterations. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s) and designing early intervention strategies, we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in circadian behavioral rhythms are detectable in an animal model of the disease. Similar to BACHDmales, BACHD females display circadian disruptions at both 3 and 6 months of age; however, deficits to BACHD female mouse activity levels, rhythm precision, and behavioral fragmentation are either delayed or less severe relative to males. These sex differe...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 7, 2015
Serine palmitoyltransferase (SPT) is a key enzyme in the first step of sphingolipid biosynthesis.... more Serine palmitoyltransferase (SPT) is a key enzyme in the first step of sphingolipid biosynthesis. Mutations in the SPTLC1 gene that encodes for SPT subunits cause hereditary sensory neuropathy type 1. However, little is understood about how mutant SPT regulates mechanisms of sensory neuron and axonal growth. Using transgenic mice overexpressing the C133W SPT mutant, we found that mutant dorsal root ganglia (DRG) during growth in vitro exhibit increased neurite length and branching, coinciding with elevated expression of actin-cross-linking proteins at the neuronal growth cone, namely phosphorylated Ezrin/Radixin/Moesin. In addition, inhibition of SPT was able to reverse the mutant phenotype. Because mutant SPT preferentially uses l-alanine over its canonical substrate l-serine, we also investigated the effects of substrate availability on DRG neurons. Supplementation with l-serine or removal of l-alanine independently restored normal growth patterns in mutant SPTLC1(C133W) DRG. Ther...
Sleep disorders are common in patients with neurogenerative diseases and manifest early in the di... more Sleep disorders are common in patients with neurogenerative diseases and manifest early in the disease process. Among a number of possible mechanisms underlying the sleep disturbances, there is evidence that dysfunction in the circadian system is a contributing factor. Focusing on a mouse model of Huntington’s disease has enabled us to determine that at the onset of symptoms, spontaneous electrical activity of neurons within the central clock is disrupted even though the molecular clockwork is still functional. These findings suggest that the fundamental deficit contributing to disordered sleep is reduced SCN output. The mechanism underlying this deficit is not yet known, but mitochondrial dysfunction and oxidative stress are likely involved. Disruption of circadian output from the SCN would be expected to have wide ranging impact on the body including SCN regulated brain regions and the heart. In fact, there is a great deal of overlap in the non-motor symptoms experienced by HD patients and the consequences of circadian disruption. This raises the possibility that the disordered sleep and circadian function experienced by HD patients may be an integral part of the disease. Furthermore, we speculate that circadian dysfunction may accelerate the pathology underlying HD. If these hypotheses are correct, we should focus on treating circadian misalignment and sleep disruptions early in disease progression.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 7, 2015
Serine palmitoyltransferase (SPT) is a key enzyme in the first step of sphingolipid biosynthesis.... more Serine palmitoyltransferase (SPT) is a key enzyme in the first step of sphingolipid biosynthesis. Mutations in the SPTLC1 gene that encodes for SPT subunits cause hereditary sensory neuropathy type 1. However, little is understood about how mutant SPT regulates mechanisms of sensory neuron and axonal growth. Using transgenic mice overexpressing the C133W SPT mutant, we found that mutant dorsal root ganglia (DRG) during growth in vitro exhibit increased neurite length and branching, coinciding with elevated expression of actin-cross-linking proteins at the neuronal growth cone, namely phosphorylated Ezrin/Radixin/Moesin. In addition, inhibition of SPT was able to reverse the mutant phenotype. Because mutant SPT preferentially uses l-alanine over its canonical substrate l-serine, we also investigated the effects of substrate availability on DRG neurons. Supplementation with l-serine or removal of l-alanine independently restored normal growth patterns in mutant SPTLC1(C133W) DRG. Ther...
The European journal of neuroscience, Jan 17, 2015
The neuropeptide vasoactive intestinal peptide is expressed at high levels in a subset of neurons... more The neuropeptide vasoactive intestinal peptide is expressed at high levels in a subset of neurons in ventral region of the suprachiasmatic nucleus (SCN). While VIP is known to be important for the synchronization of the SCN network, the role of VIP in photic regulation of the circadian system has received less attention. In the present study, we found that the light-evoked increase in electrical activity in vivo was unaltered by the loss of VIP. In the absence of VIP, the ventral SCN still exhibited NMDA-evoked responses in a brain slice preparation although the absolute levels of neural activity before and after treatment were significantly reduced. Next, we used calcium imaging techniques to determine if the loss of VIP altered the calcium influx due to retinohypothalamic tract stimulation. The magnitude of the evoked calcium influx was not reduced in the ventral SCN but did decline in the dorsal SCN regions. We examined the time course of the photic induction of Period1 in the SC...
The female reproductive cycle is gated by the circadian timing system and may be vulnerable to di... more The female reproductive cycle is gated by the circadian timing system and may be vulnerable to disruptions in the circadian system. Prior work suggests that vasoactive intestinal peptide (VIP)-expressing neurons in the suprachiasmatic nucleus (SCN) are one pathway by which the circadian clock can influence the estrous cycle, but the impact of the loss of this peptide on reproduction has not been assessed. In the present study, we first examine the impact of the genetic loss of the neuropeptide VIP on the reproductive success of female mice. Significantly, mutant females produce about half the offspring of their wild-type sisters even when mated to the same males. We also find that VIP-deficient females exhibit a disrupted estrous cycle; that is, ovulation occurs less frequently and results in the release of fewer oocytes compared with controls. Circadian rhythms of wheel-running activity are disrupted in the female mutant mice, as is the spontaneous electrical activity of dorsal SCN...
Sleep disorders are common in patients with neurogenerative diseases and manifest early in the di... more Sleep disorders are common in patients with neurogenerative diseases and manifest early in the disease process. Among a number of possible mechanisms underlying the sleep disturbances, there is evidence that dysfunction in the circadian system is a contributing factor. Focusing on a mouse model of Huntington's disease has enabled us to determine that at the onset of symptoms, spontaneous electrical activity of neurons within the central clock is disrupted even though the molecular clockwork is still functional. These findings suggest that the fundamental deficit contributing to disordered sleep is reduced SCN output. The mechanism underlying this deficit is not yet known, but mitochondrial dysfunction and oxidative stress are likely involved. Disruption of circadian output from the SCN would be expected to have wide ranging impact on the body including SCN regulated brain regions and the heart. In fact, there is a great deal of overlap in the non-motor symptoms experienced by HD...
The ability to generate intrinsic circadian rhythms in electrical activity appears to be a key pr... more The ability to generate intrinsic circadian rhythms in electrical activity appears to be a key property of central pacemaker neurons and one essential to the function of the circadian timing system. Previous work has demonstrated that suprachiasmatic nucleus (SCN) neurons express the fast delayed rectifier (FDR) potassium current and raise questions about the function of this current. Here, we report that mice lacking both Kcnc1 and Kcnc2 genes [double knockout (dKO)] fail to express the Kv3.1 and 3.2 channels in the SCN as well as exhibit a greatly reduced FDR current. SCN neurons from these dKO mice exhibit reduced spontaneous activity during the day as well as reduced NMDA-evoked excitatory responses during the night. Interestingly, the daily rhythm in PER2 expression in the SCN was not altered in the dKO mice, although the photic induction of c-Fos was attenuated. Behaviorally, the dKO mice exhibited extremely disrupted daily rhythms in wheel-running behavior. In a light/dark cycle, some of the dKO mice were arrhythmic, whereas others expressed a diurnal rhythm with low amplitude and significant activity during the day. When placed in constant darkness, the dKO mice exhibited lowamplitude, fragmented rhythms and attenuated light responses. Together, these data are consistent with the hypothesis that the FDR current is critical for the generation of robust circadian rhythms in behavior as well as the synchronization of the circadian system to the photic environment.
Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, heredi... more Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, hereditary sensory, and autonomic neuropathy type I (HSAN1). We previously reported that mice bearing a transgene-expressing mutant SPTLC1 (tgSPTLC1 C133W) show a reduction in SPT activity and hyperpathia at 10 months of age. Now analyzed at a later age, we find these mice develop sensory loss with a distal small fiber neuropathy and peripheral myelinopathy. This phenotype is largely reversed when these mice are crossed with transgenic mice overexpressing wild-type SPTLC1 showing that the mutant SPTLC1 protein is not inherently toxic. Simple loss of SPT activity also cannot account for the HSAN1 phenotype, since heterozygous SPTLC1 knockout mice have reduced SPT activity but are otherwise normal. Rather, the presence of two newly identified, potentially deleterious deoxysphingoid bases in the tgSPTLC1 C133W , but not in the wild-type, double-transgenic tgSPTLC1 WT ϩ C133W or SPTLC1 ϩ/Ϫ mice, suggests that the HSAN1 mutations alter amino acid selectivity of the SPT enzyme such that palmitate is condensed with alanine and glycine, in addition to serine. This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.
Sleep disorders are nearly ubiquitous among patients with Parkinson's disease (PD), and they mani... more Sleep disorders are nearly ubiquitous among patients with Parkinson's disease (PD), and they manifest early in the disease process. While there are a number of possible mechanisms underlying these sleep disturbances, a primary dysfunction of the circadian system should be considered as a contributing factor. Our laboratory's behavioral phenotyping of a well-validated transgenic mouse model of PD reveals that the electrical activity of neurons within the master pacemaker of the circadian system, the suprachiasmatic nuclei (SCN), is already disrupted at the onset of motor symptoms, although the core features of the intrinsic molecular oscillations in the SCN remain functional. Our observations suggest that the fundamental circadian deficit in these mice lies in the signaling output from the SCN, which may be caused by known mechanisms in PD etiology: oxidative stress and mitochondrial disruption. Disruption of the circadian system is expected to have pervasive effects throughout the body and may itself lead to neurological and cardiovascular disorders. In fact, there is much overlap in the non-motor symptoms experienced by PD patients and in the consequences of circadian disruption. This raises the possibility that the sleep and circadian dysfunction experienced by PD patients may not merely be a subsidiary of the motor symptoms, but an integral part of the disease. Furthermore, we speculate that circadian dysfunction can even accelerate the pathology underlying PD. If these hypotheses are correct, more aggressive treatment of the circadian misalignment and sleep disruptions in PD patients early in the pathogenesis of the disease may be powerful positive modulators of disease progression and patient quality of life.
Many patients with Huntington's disease (HD) exhibit disturbances in their daily cycle of sleep a... more Many patients with Huntington's disease (HD) exhibit disturbances in their daily cycle of sleep and wake as part of their symptoms. These patients have difficulty sleeping at night and staying awake during the day, which has a profound impact on the quality of life of the patients and their care-givers. In the present study, we examined diurnal and circadian rhythms of four models of HD including the BACHD, CAG 140 knock-in and R6/2 CAG 140 and R6/2 CAG 250 lines of mice. The BACHD and both R6/2 lines showed profound circadian phenotypes as measured by wheel-running activity. Focusing on the BACHD line for further analysis, the amplitude of the rhythms in the BACHD mice declined progressively with age. In addition, the circadian regulation of heart rate and body temperature in freely behaving BACHD mice were also disrupted. Furthermore, the distribution of sleep as well as the autonomic regulation of heart rate was disrupted in this HD model. To better understand the mechanistic underpinnings of the circadian disruption, we used electrophysiological tools to record from neurons within the central clock in the suprachiasmatic nucleus (SCN). The BACHD mice exhibit reduced rhythms in spontaneous electrical activity in SCN neurons. Interestingly, the expression of the clock gene PERIOD2 was not altered in the SCN of the BACHD line. Together, this data is consistent with the hypothesis that the HD mutations interfere with the expression of robust circadian rhythms in behavior and physiology. The data raise the possibility that the electrical activity within the central clock itself may be altered in this disease.
Compelling reasons to study the role of sex in the circadian system include the higher rates of s... more Compelling reasons to study the role of sex in the circadian system include the higher rates of sleep disorders in women than in men and evidence that sex steroids modulate circadian control of locomotor activity. To address the issue of sex differences in the circadian system, we examined daily and circadian rhythms in wheel-running activity, electrical activity within the suprachiasmatic nucleus, and PER2::LUC-driven bioluminescence of gonadally-intact adult male and female C57BL/6J mice. We observed greater precision of activity onset in 12-hour light, 12-hour dark cycle for male mice, longer activity duration in 24 hours of constant darkness for female mice, and phase-delayed PER2::LUC bioluminescence rhythm in female pituitary and liver. Next, in order to investigate whether sex differences in behavior are sex chromosome or gonadal sex dependent, we used the 4 core genotypes (FCG) mouse model, in which sex chromosome complement is independent of gonadal phenotype. Gonadal males...
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Papers by Dika Kuljis