Neuropeptides of the human magnocellular hypothalamus.

Hypothalamic magnocellular nuclei with their large secretory neurons are unique and phylogenetically conserved brain structures involved in the continual regulation of important homeostatic and autonomous functions in vertebrate species. Both canonical and newly identified neuropeptides have a broad spectrum of physiological activity at the hypothalamic neuronal circuit level located within the supraoptic (SON) and paraventricular (PVN) nuclei. Magnocellular neurons express a variety of receptors for neuropeptides and neurotransmitters and therefore receive numerous excitatory and inhibitory inputs from important subcortical neural areas such as limbic and brainstem populations. These unique cells are also densely innervated by axons from other hypothalamic nuclei. The vast majority of neurochemical maps pertain to animal models, mainly the rodent hypothalamus, however accumulating preliminary anatomical structural studies have revealed the presence and distribution of several neuropeptides in the human magnocellular nuclei. This review presents a novel and comprehensive evidence based evaluation of neuropeptide expression in the human SON and PVN. Collectively this review aims to cast a new, medically oriented light on hypothalamic neuroanatomy and contribute to a better understanding of the mechanisms responsible for neuropeptide-related physiology and the nature of possible neuroendocrinal interactions between local regulatory pathways.

Plasticity in Intrinsic Excitability of Hypothalamic Magnocellular Neurosecretory Neurons in Late-Pregnant and Lactating Rats.

Oxytocin and vasopressin secretion from the posterior pituitary gland are required for normal pregnancy and lactation. Oxytocin secretion is relatively low and constant under basal conditions but becomes pulsatile during birth and lactation to stimulate episodic contraction of the uterus for delivery of the fetus and milk ejection during suckling. Vasopressin secretion is maintained in pregnancy and lactation despite reduced osmolality (the principal stimulus for vasopressin secretion) to increase water retention to cope with the cardiovascular demands of pregnancy and lactation. Oxytocin and vasopressin secretion are determined by the action potential (spike) firing of magnocellular neurosecretory neurons of the hypothalamic supraoptic and paraventricular nuclei. In addition to synaptic input activity, spike firing depends on intrinsic excitability conferred by the suite of channels expressed by the neurons. Therefore, we analysed oxytocin and vasopressin neuron activity in anaesthetised non-pregnant, late-pregnant, and lactating rats to test the hypothesis that intrinsic excitability of oxytocin and vasopressin neurons is increased in late pregnancy and lactation to promote oxytocin and vasopressin secretion required for successful pregnancy and lactation. Hazard analysis of spike firing revealed a higher incidence of post-spike hyperexcitability immediately following each spike in oxytocin neurons, but not in vasopressin neurons, in late pregnancy and lactation, which is expected to facilitate high frequency firing during bursts. Despite lower osmolality in late-pregnant and lactating rats, vasopressin neuron activity was not different between non-pregnant, late-pregnant, and lactating rats, and blockade of osmosensitive ΔN-TRPV1 channels inhibited vasopressin neurons to a similar extent in non-pregnant, late-pregnant, and lactating rats. Furthermore, supraoptic nucleus ΔN-TRPV1 mRNA expression was not different between non-pregnant and late-pregnant rats, suggesting that sustained activity of ΔN-TRPV1 channels might maintain vasopressin neuron activity to increase water retention during pregnancy and lactation.

An Angiotensin-Responsive Connection from the Lamina Terminalis to the Paraventricular Nucleus of the Hypothalamus Evokes Vasopressin Secretion to Increase Blood Pressure in Mice.

Blood pressure is controlled by endocrine, autonomic, and behavioral responses that maintain blood volume and perfusion pressure at levels optimal for survival. Although it is clear that central angiotensin type 1a receptors (AT1aR; encoded by the Agtr1a gene) influence these processes, the neuronal circuits mediating these effects are incompletely understood. The present studies characterize the structure and function of AT1aR neurons in the lamina terminalis (containing the median preoptic nucleus and organum vasculosum of the lamina terminalis), thereby evaluating their roles in blood pressure control. Using male Agtr1a-Cre mice, neuroanatomical studies reveal that AT1aR neurons in the area are largely glutamatergic and send projections to the paraventricular nucleus of the hypothalamus (PVN) that appear to synapse onto vasopressin-synthesizing neurons. To evaluate the functionality of these lamina terminalis AT1aR neurons, we virally delivered light-sensitive opsins and then optogenetically excited or inhibited the neurons while evaluating cardiovascular parameters or fluid intake. Optogenetic excitation robustly elevated blood pressure, water intake, and sodium intake, while optogenetic inhibition produced the opposite effects. Intriguingly, optogenetic excitation of these AT1aR neurons of the lamina terminalis also resulted in Fos induction in vasopressin neurons within the PVN and supraoptic nucleus. Further, within the PVN, selective optogenetic stimulation of afferents that arise from these lamina terminalis AT1aR neurons induced glutamate release onto magnocellular neurons and was sufficient to increase blood pressure. These cardiovascular effects were attenuated by systemic pretreatment with a vasopressin-1a-receptor antagonist. Collectively, these data indicate that excitation of lamina terminalis AT1aR neurons induces neuroendocrine and behavioral responses that increase blood pressure.SIGNIFICANCE STATEMENT Hypertension is a widespread health problem and risk factor for cardiovascular disease. Although treatments exist, a substantial percentage of patients suffer from "drug-resistant" hypertension, a condition associated with increased activation of brain angiotensin receptors, enhanced sympathetic nervous system activity, and elevated vasopressin levels. The present study highlights a role for angiotensin Type 1a receptor expressing neurons located within the lamina terminalis in regulating endocrine and behavioral responses that are involved in maintaining cardiovascular homeostasis. More specifically, data presented here reveal functional excitatory connections between angiotensin-sensitive neurons in the lamina terminals and vasopressin neurons in the paraventricular nucleus of the hypothalamus, and further indicate that activation of this circuit raises blood pressure. These neurons may be a promising target for antihypertensive therapeutics.

Effects of Delphinidin on Pathophysiological Signs of Nucleus Basalis of Meynert Lesioned Rats as Animal Model of Alzheimer Disease.

Alzheimer's disease (AD) is an advanced neurodegenerative disorder greatly accompanied by cognitive deficits, oxidative stress, inflammation, amyloid plaques deposition, and acetylcholinesterase (AChE) hyper-activation. Growing evidence suggests natural compounds with antioxidant and anti-inflammatory features improve pathophysiological signs of AD. The present study was designed to investigate the effects of Delphinidin (25, 50 mg/kg) as an anthocyanidin on spatial memory impairment and AD hallmarks such as hippocampal AChE activity, amyloid plaques deposition, oxidative stress and expression of amyloid precursor protein (APP), AChE, and amyloid beta (Aß) proteins in nucleus basalis of Meynert (NBM) lesioned rats as the most prevalent animal model of AD. Interestingly, Delphinidin-treated animals showed a significant decrease in escape latency and distance moved. Furthermore, in probe test, NBM lesioned rats treated with both doses of Delphinidin spent more time in the target quadrant zone in Morris water maze task. It could also interact with catalytic site of AChE enzyme and inhibits acetylcholine hydrolysis in in vitro and in vivo conditions. In addition, Delphinidin could scavenge additional produced reactive oxygen molecules dose dependently. Our immunoblotting analysis confirmed high dose of Delphinidin reduced AChE, APP and Aß contents in AD model. Staining of hippocampus tissue revealed that Delphinidin treatment decreased amyloid plaques formation in NBM lesion rats. It seems that Delphinidin is a plate-like molecule intercalated between ß-plated sheets related to Aß molecules and inhibited amyloid fibril formation. Altogether, Delphinidin and Delphinidin-rich fruits could be suggested as a therapeutic adjuvant in AD and other related cognitive disorders.

Activation of GSK-3 disrupts cholinergic homoeostasis in nucleus basalis of Meynert and frontal cortex of rats.

The cholinergic impairment is an early marker in Alzheimer's disease (AD), while the mechanisms are not fully understood. We investigated here the effects of glycogen synthase kinse-3 (GSK-3) activation on the cholinergic homoeostasis in nucleus basalis of Meynert (NBM) and frontal cortex, the cholinergic enriched regions. We activated GSK-3 by lateral ventricular infusion of wortmannin (WT) and GF-109203X (GFX), the inhibitors of phosphoinositol-3 kinase (PI3-K) and protein kinase C (PKC), respectively, and significantly decreased the acetylcholine (ACh) level via inhibiting choline acetyl transferase (ChAT) rather than regulating acetylcholinesterase (AChE). Neuronal axonal transport was disrupted and ChAT accumulation occurred in NBM and frontal cortex accompanied with hyperphosphorylation of tau and neurofilaments. Moreover, ChAT expression decreased in NBM attributing to cleavage of nuclear factor-κB/p100 into p52 for translocation into nucleus to lower ChAT mRNA level. The cholinergic dysfunction could be mimicked by overexpression of GSK-3 and rescued by simultaneous administration of LiCl or SB216763, inhibitors of GSK-3. Our data reveal the molecular mechanism that may underlie the cholinergic impairments in AD patients.

Selective specificity of calcium-binding proteins calbindin and calretinin expression in the magnocellular neurosecretory hypothalamic nuclei of tortoises and turtles.

We have studied the distribution of calcium-binding proteins in the magnocellular neurosecretory nuclei of nonapeptidergic neurosecretory nuclei of the preoptic-hypothalamic complex in a tortoise (Testudo horsfieldi) and a pond turtle (Emys orbicularis) using immunohistochemistry. We have found that different types of cells in the paraventricular and supraoptic nuclei predominantly express calbindin and, to a lesser extent, calretinin, but not parvalbumin. The selective calbindin/calretinin control of the neurohormone secretion in these hypothalamic nuclei is an evolutionary conservative feature typical of reptiles and mammals.

A direct GABAergic output from the basal ganglia to frontal cortex.

The basal ganglia are phylogenetically conserved subcortical nuclei necessary for coordinated motor action and reward learning. Current models postulate that the basal ganglia modulate cerebral cortex indirectly via an inhibitory output to thalamus, bidirectionally controlled by direct- and indirect-pathway striatal projection neurons (dSPNs and iSPNs, respectively). The basal ganglia thalamic output sculpts cortical activity by interacting with signals from sensory and motor systems. Here we describe a direct projection from the globus pallidus externus (GP), a central nucleus of the basal ganglia, to frontal regions of the cerebral cortex (FC). Two cell types make up the GP-FC projection, distinguished by their electrophysiological properties, cortical projections and expression of choline acetyltransferase (ChAT), a synthetic enzyme for the neurotransmitter acetylcholine (ACh). Despite these differences, ChAT(+) cells, which have been historically identified as an extension of the nucleus basalis, as well as ChAT(-) cells, release the inhibitory neurotransmitter GABA (γ-aminobutyric acid) and are inhibited by iSPNs and dSPNs of dorsal striatum. Thus, GP-FC cells comprise a direct GABAergic/cholinergic projection under the control of striatum that activates frontal cortex in vivo. Furthermore, iSPN inhibition of GP-FC cells is sensitive to dopamine 2 receptor signalling, revealing a pathway by which drugs that target dopamine receptors for the treatment of neuropsychiatric disorders can act in the basal ganglia to modulate frontal cortices.

Neuroprotective activity of hydroponic Teucrium polium following bilateral ovariectomy.

Ovariectomy is known as "surgical menopause" with decreased levels of estrogen in female rodents. Its reported risks and adverse effects include cognitive impairment. The action of hydroponic Teucrium polium on nucleus basalis of Meynert (bnM) neurons following 6 weeks of ovariectomy was carried out. The analysis of spike activity was observed by on-line selection and the use of a software package. Early and late tetanic, - posttetanic potentiation and depression of neurons to high frequency stimulation of hippocampus were studied. The complex averaged peri-event time and frequency histograms were constructed. The histochemical study of the activity of Са(2+)-dependent acid phosphatase was observed. In conditions of hydroponic Teucrium polium administration, positive changes in neurons and gain of metabolism leading to cellular survival were revealed. The administration of Teucrium polium elicited neurodegenerative changes in bnM.

Slowly emerging glycinergic transmission enhances inhibition in the sound localization pathway of the avian auditory system.

Localization of low-frequency acoustic stimuli is processed in dedicated neural pathways where coincidence-detecting neurons compare the arrival time of sound stimuli at the two ears, or interaural time disparity (ITD). ITDs occur in the submillisecond range, and vertebrates have evolved specialized excitatory and inhibitory circuitry to compute these differences. Glycinergic inhibition is a computationally significant and prominent component of the mammalian ITD pathway. However, evidence for glycinergic transmission is limited in birds, where GABAergic inhibition has been thought to be the dominant or exclusive inhibitory transmitter. Indeed, previous work showed that GABA antagonists completely eliminate inhibition in avian nuclei specialized for processing temporal features of sound, nucleus magnocellularis (NM) and nucleus laminaris (NL). However, more recent work shows that glycine is coexpressed with GABA in synaptic terminals apposed to neurons in both nuclei (Coleman WL, Fischl MJ, Weimann SR, Burger RM. J Neurophysiol 105: 2405-2420, 2011; Kuo SP, Bradley LA, Trussell LO. J Neurosci 29: 9625-9634, 2009). Here we show complementary evidence of functional glycine receptor (GlyR) expression in NM and NL. Additionally, we show that glycinergic input can be evoked under particular stimulus conditions. Stimulation at high but physiologically relevant rates evokes a slowly emerging glycinergic response in NM and NL that builds over the course of the stimulus. Glycinergic response magnitude was stimulus rate dependent, representing 18% and 7% of the total inhibitory current in NM and NL, respectively, at the end of the 50-pulse, 200-Hz stimulus. Finally, we show that the glycinergic component is functionally relevant, as its elimination reduced inhibition of discharges evoked by current injection into NM neurons.

[Lamellar complex changes in the human basal forebrain and hypothalamic nuclei neurons in different age groups].

In the present study the lamellar complex (LC, Golgi complex) changes in the major cholinergic nuclei of the human basal forebrain - the nucleus basalis of Meynert (NBM), the vertical nucleus of the diagonal band of Broca (VDB) and hypothalamus--the tuberomamillary (TMN), the medial mammillary (MMN) and supraoptic (SON) nuclei were analyzed considering the WHO aging classification. The increase in the size of the LC was present in NBM, MMN and SON in the 3rd age group of elderly people (60-74 years of age), in the VDB--in the 4th group (75-89 years of age), whereas in the TMN LC changes were not apparent. In conclusion, the WHO aging classification reflects the LC values age ranges and can be used to estimate age-related alterations of this parameter. The increase in the size of the neuronal LC in elderly people may represent the compensatory reaction of neuroplasticity triggered by the aging process.

Melanocortin 4 receptor distribution in the human hypothalamus.

OBJECTIVE: The melanocortin 4 receptor (MC4R) is an essential regulator of energy homeostasis and metabolism, and MC4R mutations represent the most prevalent monogenetic cause of obesity in humans known to date. Hypothalamic MC4Rs in rodents are well characterized in neuroanatomical and functional terms, but their expression pattern in the human hypothalamus is unknown. DESIGN AND METHODS: To determine the topographic distribution and identity of cells expressing MC4R mRNA in the human hypothalamus, locked nucleic acid in situ hybridization was performed on nine human postmortem hypothalami. In addition, co-expression of MC4R with glial fibrillary acidic protein (GFAP), vasopressin/oxytocin (AVP/OXT), corticotropin-releasing hormone (CRH), neuropeptide Y (NPY), agouti-related protein (AgRP), and α-melanocyte stimulating hormone (α-MSH) was examined. RESULTS: Most intense MC4R mRNA expression was present in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), and the nucleus basalis of Meynert. Most MC4R-positive cells in the SON also expressed AVP/OXT. Co-expression with AVP/OXT in the PVN was less abundant. We did not observe co-expression of MC4R mRNA and GFAP, CRH, NPY, AgRP, or α-MSH. However, fiber-like staining of NPY, AgRP, and α-MSH was found adjacent to MC4R-positive cells in the PVN. CONCLUSION: Expression of MC4R mRNA in the human hypothalamus is widespread and in close approximation to endogenous MC4R binding partners AgRP and α-MSH.

[Effect of tanshinone IIA on the change of calcium current induced by beta-amyloid protein 25-35 in neurons of nucleus basalis of Meynert].

OBJECTIVE: To explore the effect of tanshinone IIA (TanIIA) on calcium current induced by beta-amyloid protein 25-35 (Abeta25-35) in neurons of nucleus basalis of Meynert (nbM). METHODS: Cell acute dissociated technique and the whole-cell recording model of patch-clamp technique of single-cell were used. The voltage-dependent calcium current in neurons of nbM was recorded in SD rats first. Then the effect of TanIIA on the voltage-dependent calcium current in the neurons was assayed. The change of calcium current induced by Abeta25-35 as well as the effect of TanIIA on the change of calcium current induced by Abeta25-35 in neurons of nbM were analyzed. RESULTS: Extracellular fluid containing different concentrations of TanIIA was irrigated, respectively. The peak current did not change obviously. There was no difference in current density between the TanIIA group and the control group at 0 mV (P>0.05). Extracellular fluid containing 200 nmol/L Abeta25-35 was irrigated after the normal calcium current recorded under whole patch clamp, and the peak current changed obviously. There was distinct difference in the current density between the Abeta group and the control group at 0 mV (P<0.05). Extracellular fluid containing Abeta25-35 and different concentrations of TanIIA were irrigated after the normal calcium current was recorded under whole patch clamp, respectively, and the peak current did not change. There was no difference in current density between the TanIIA +Abeta group and the control group at 0 mV (P>0.05). CONCLUSION: In vitro, TanIIA could inhibit the calcium current amplification induced by Abeta25-35 in neurons of nbM. TanIIA may protect neurons against the toxicity of Abeta and decrease the inward flow of Ca(2+).

Induction of c-Fos expression by electrical stimulation of the nucleus basalis magnocellularis.

The present study examined the expression of the immediate-early gene c-fos in different brain regions following a single 20-min session of unilateral electrical stimulation of the nucleus basalis magnocellularis (NBM). Current findings confirm that NBM stimulation provides specific activation of several cortical and subcortical regions closely related to the NBM and involved in learning and memory processes, such as the cingulate, parietal, piriform and perirhinal cortices, dorsal subiculum, and the parafascicular, central lateral and central medial nuclei of the thalamus. In contrast, NBM stimulation did not increase c-Fos expression in some expected areas that receive direct NBM projections such as the entorhinal cortex or amygdala nuclei. Results are discussed in terms of the possibility that NBM electrical stimulation facilitates learning by inducing neural changes related to transcription factors such as c-Fos.

Estrogen enhances expression of the complement C5a receptor and the C5a-agonist evoked calcium influx in hormone secreting neurons of the hypothalamus.

In the present study we examined presence of the complement C5a receptor (C5aR) in hypothalamic neurosecretory neurons of the rodent brain and effect of estrogen on C5aR expression. Whole cell patch clamp measurements revealed that magnocellular neurons in the supraoptic and paraventricular nuclei of hypothalamic slices of the rats responded to the C5aR-agonist PL37-MAP peptide with calcium ion current pulses. Gonadotropin-releasing hormone (GnRH) producing neurons in slices of the preoptic area of the mice also reacted to the peptide treatment with inward calcium current. PL37-MAP was able to evoke the inward ion current of GnRH neurons in slices from ovariectomized animals. The amplitude of the inward pulses became higher in slices obtained from 17beta-estradiol (E2) substituted mice. Calcium imaging experiments demonstrated that PL37-MAP increased the intracellular calcium content in the culture of the GnRH-producing GT1-7 cell line in a concentration-dependent manner. Calcium imaging also showed that E2 pretreatment elevated the PL37-MAP evoked increase of the intracellular calcium content in the GT1-7 cells. The estrogen receptor blocker Faslodex in the medium prevented the E2-evoked increase of the PL37-MAP-triggered elevation of the intracellular calcium content in the GT1-7 cells demonstrating that the effect of E2 might be related to the presence of estrogen receptor. Real-time PCR experiments revealed that E2 increased the expression of C5aR mRNA in GT1-7 neurons, suggesting that an increased C5aR synthesis could be involved in the estrogenic modulation of calcium response. These data indicate that hypothalamic neuroendocrine neurons can integrate immune and neuroendocrine functions. Our results may serve a better understanding of the inflammatory and neurodegeneratory diseases of the hypothalamus and the related neuroendocrine and autonomic compensatory responses.

Changes in neural activity associated with a surprising change in the predictive validity of a conditioned stimulus.

Changes in how well a conditioned stimulus (CS) predicts future events can alter the amount of attention paid to that cue. For example, the unexpected violation of a previously established relationship between a CS and another stimulus can increase attentional processing and subsequent conditioning to that cue [J.M. Pearce & G. Hall (1980)Psych. Rev., 106, 532-552]. Previous lesion studies have implicated the central nucleus of the amygdala (CN) and basal forebrain corticopetal cholinergic system in mediating surprise-induced changes in attention. Here, expression of the immediate-early gene c-fos was used to determine which cortical targets of the basal forebrain cholinergic system are activated during an increase in attentional processing. Consistent with previous studies, increased Fos expression was observed in the posterior parietal cortex (PPC) when a visual stimulus no longer reliably predicted occurrence of a tone. Similar results were observed in the secondary auditory cortex; however, there were no significant changes in Fos expression in other auditory or visual cortices or in other cortical association areas that have been implicated in attentional function (frontal, cingulate or retrosplenial cortex). These findings support the notion that the PPC is the primary cortical component of a neural system mediating incremental changes in attention. In addition, an increase in Fos-positive cells was detected in the substantia innominata/nucleus basalis and the CN at the time of surprise. An opposite pattern of results was observed in the basal lateral nucleus of the amygdala, providing evidence for different stimulus-processing mechanisms in regions of the amygdala.

Cholinergic neuronal deficits in CADASIL.

BACKGROUND AND PURPOSE: Previous evidence from MRI and acetylcholinesterase histochemistry suggests cholinergic fibers are affected in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: As a measure of cholinergic function, we assessed choline acetyltransferase (ChAT) activities in the frontal and temporal neocortices and the immunocytochemical distribution of ChAT and p75 neurotrophin receptor (P75(NTR)) by in vitro imaging in the nucleus basalis of Meynert of CADASIL subjects. RESULTS: ChAT activities were significantly reduced by 60% to 70% in frontal and temporal cortices of CADASIL cases, as were ChAT and P75(NTR) immunoreactivities in the nucleus basalis. CONCLUSIONS: Our findings suggest cholinergic neuronal impairment in CADASIL and implicate cholinomimetic therapy for subcortical vascular dementias.

SMN, the product of the spinal muscular atrophy-determining gene, is expressed widely but selectively in the developing human forebrain.

The expression pattern of the survival motor neuron (SMN) protein has been investigated immunohistochemically in the human fetal forebrain from 14 to 38 weeks of gestation. Mutations in the SMN gene cause spinal muscular atrophy (SMA), an autosomal recessive disease characterized by degeneration of lower motor neurons in the spinal cord leading to progressive muscle wasting. SMN is a multifunctional protein and has been implicated in diverse cytoplasmic and nuclear processes. The monoclonal murine SMN antibody used in this study recognized a major band at approximately 34 kDa. In spinal cord anterior horn motor neurons at 13 weeks of gestation, the soma, proximal neurites, and nucleus were immunostained. In the nucleus, SMN immunolabeling was observed at the nuclear membrane, at the nucleolus, and at dot-like structures in the nucleoplasm likely to be coiled bodies and gems. In the fetal forebrain, SMN was immunodetected as early as 14 weeks of gestation. From 14 to 24 weeks of gestation, intense immunostaining was observed in the basal nucleus of Meynert, a major source of cholinergic afferents to the cortex. Less intensely labeled cells at lower packing density were also observed in the thalamus, reticular and perireticular nucleus, globus pallidus, hippocampus, amygdala, and enthorinal cortex. Immunolabeled cells were still detectable at 38 gestational weeks, the latest time point investigated. These findings provide an anatomical basis for future investigations of SMN functions during brain development and for the neuropathological characterization of severe SMA cases.

Gene expression in the rat brain during sleep deprivation and recovery sleep: an Affymetrix GeneChip study.

Previous studies have demonstrated that macromolecular synthesis in the brain is modulated in association with the occurrence of sleep and wakefulness. Similarly, the spectral composition of electroencephalographic activity that occurs during sleep is dependent on the duration of prior wakefulness. Since this homeostatic relationship between wake and sleep is highly conserved across mammalian species, genes that are truly involved in the electroencephalographic response to sleep deprivation might be expected to be conserved across mammalian species. Therefore, in the rat cerebral cortex, we have studied the effects of sleep deprivation on the expression of immediate early gene and heat shock protein mRNAs previously shown to be upregulated in the mouse brain in sleep deprivation and in recovery sleep after sleep deprivation. We find that the molecular response to sleep deprivation and recovery sleep in the brain is highly conserved between these two mammalian species, at least in terms of expression of immediate early gene and heat shock protein family members. Using Affymetrix Neurobiology U34 GeneChips , we also screened the rat cerebral cortex, basal forebrain, and hypothalamus for other genes whose expression may be modulated by sleep deprivation or recovery sleep. We find that the response of the basal forebrain to sleep deprivation is more similar to that of the cerebral cortex than to the hypothalamus. Together, these results suggest that sleep-dependent changes in gene expression in the cerebral cortex are similar across rodent species and therefore may underlie sleep history-dependent changes in sleep electroencephalographic activity.

Sundowning and circadian rhythm disorders in dementia.

Sleep disorders and disruptive nocturnal behaviours are commonly reported in people with senile dementia and present both a significant clinical problem and a cause of increased stress for caregivers. Neuronal degeneration of cholinergic Nucleus basalis Meynert (NBM) neurons promote rest-activity disturbance and Sundowning in Alzheimer's disease. NBM neurons modulate the activity of the mainly cholinergic suprachiasmatic nucleus (SCN) and the induction of NONREM sleep. Sundowning might be explained as a syndrome occurring when arousal is to be processed while the neocortex is already turned "off" to (NONREM) sleep. The therapeutic measures should thus primarily be aimed at the stimulation of the circadian system and enforcing "external Zeitgebers". Pharmacologically, application of cholinergic enhancers i.e. cholinesterase inhibitors and melatonin supports and should stabilize the weakened structures.

Neurochemical correlates of differential neuroprotection by long-term dietary creatine supplementation.

Dietary supplementation with creatine has proven to be beneficial in models of acute and chronic neurodegeneration. We report here data on the neurochemical correlates of differential protection of long-term creatine supplementation in two models of excitotoxicity in rats, as well as in the mouse model for ALS (G93A mice). In rats, the fall in cholinergic and GABAergic markers due to the excitotoxic death of intrinsic neurons caused by intrastriatal infusion of the neurotoxin, ibotenic acid, was significantly prevented by long-term dietary supplementation with creatine. On the contrary, creatine was unable to recover a cholinergic marker in the cortex of rats subjected to the excitotoxic death of the cholinergic basal forebrain neurons. In G93A mice, long-term creatine supplementation marginally but significantly increased mean lifespan, as previously observed by others, and reverted the cholinergic deficit present in some forebrain areas at an intermediate stage of the disease. In both rats and mice, creatine supplementation increased the activity of the GABAergic enzyme, glutamate decarboxylase, in the striatum but not in other brain regions. The present data point at alterations of neurochemical parameters marking specific neuronal populations, as a useful way to evaluate neuroprotective effects of long-term creatine supplementation in animal models of neurodegeneration.