Salvador Huitron-Resendiz

Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects.

Arousal and anxiety are behavioral responses that involve complex neurocircuitries and multiple neurochemical components. Here, we report that a neuropeptide, neuropeptide S (NPS), potently modulates wakefulness and could also regulate anxiety. NPS acts by activating its cognate receptor (NPSR) and inducing mobilization of intracellular Ca2+. The NPSR mRNA is widely distributed in the brain, including the amygdala and the midline thalamic nuclei. Central administration of NPS increases locomotor activity in mice and decreases paradoxical (REM) sleep and slow wave sleep in rats. NPS was further shown to produce anxiolytic-like effects in mice exposed to four different stressful paradigms. Interestingly, NPS is expressed in a previously undefined cluster of cells located between the locus coeruleus (LC) and Barringtons nucleus. These results indicate that NPS could be a new modulator of arousal and anxiety. They also show that the LC region encompasses distinct nuclei expressing different arousal-promoting neurotransmitters.

5-HT7 Receptor Inhibition and Inactivation Induce Antidepressantlike Behavior and Sleep Pattern

BACKGROUND The 5-hydroxytryptamine7 receptor (5-HT7) is implicated in circadian rhythm phase resetting, and 5-HT7 receptor-selective antagonists alter rapid eye movement (REM) sleep parameters in a pattern opposite from those in patients with clinical depression. METHODS As sleep, circadian rhythm, and mood regulation are related, we examined 5-HT7 receptor knockout mice in two behavioral models of depression. The forced swim and tail suspension tests are highly predictive for antidepressant drug activity. RESULTS Unmedicated 5-HT7-/- mice showed decreased immobility in both tests, consistent with an antidepressantlike behavior. The selective 5-HT7 receptor antagonist SB-269970 also decreased immobility. The selective serotonin reuptake inhibitor citalopram, a widely used antidepressant, decreased immobility in both 5-HT7+/+ and 5-HT7-/- mice in the tail suspension test, suggesting that it utilizes an independent mechanism. The 5-HT7-/- mice spent less time in and had less frequent episodes of REM sleep, also consistent with an antidepressantlike state. CONCLUSIONS The 5-HT7 receptor might have a role in mood disorders and antagonists might have therapeutic value as antidepressants.

Profound increase in sensitivity to glutamatergic- but not cholinergic agonist-induced seizures in transgenic mice with astrocyte production of IL-6.

Transgenic mice with glial fibrillary acidic protein (GFAP) promoter driven‐astrocyte production of the cytokines interleukin‐6 (IL‐6) and tumor necrosis factor (TNF) were used to determine whether the pre‐existing production of these cytokines in vivo might modulate the sensitivity of neurons to excitotoxic agents. Low doses of kainic acid (5 mg/kg) that produced little or no behavioral or electroencephalogram (EEG) alterations in wild type or glial fibrillary acidic protein (GFAP)‐TNF animals induced severe tonic‐clonic seizures and death in GFAP‐IL6 transgenic mice of 2 or 6 months of age. GFAP‐IL6 mice were also significantly more sensitive to N‐methyl‐D‐aspartate (NMDA)‐ but not pilocarpine‐induced seizures. Kainic acid uptake in the brain of the GFAP‐IL6 mice was higher in the cerebellum but not in other regions. Kainic acid binding in the brain of GFAP‐IL6 mice had a similar distribution and density as wild type controls. In the hippocampus of GFAP‐IL6 mice that survived low dose kainic acid, there was no change in the extent of either neurodegeneration or astrocytosis. Immunostaining revealed degenerative changes in gamma aminobutyric acid (GABA)‐ and parvalbumin‐positive neurons in the hippocampus of 2‐month‐old GFAP‐IL6 mice which progressed to the loss of these cells at 6 months of age. Thus, GFAP‐IL6 but not GFAP‐TNF mice showed markedly enhanced sensitivity to glutamatergic‐ but not cholinergic‐induced seizures and lethality. This may relate, in part, to a compromise of inhibitory interneuron function. Therefore, pre‐existing IL‐6 production and inflammation in the central nervous system (CNS) not only causes spontaneous neurodegeneration but also synergizes with other neurotoxic insults to induce more severe acute functional neurological impairment.

Highly Activated CD8+ T Cells in the Brain Correlate with Early Central Nervous System Dysfunction in Simian Immunodeficiency Virus Infection

One of the consequences of HIV infection is damage to the CNS. To characterize the virologic, immunologic, and functional factors involved in HIV-induced CNS disease, we analyzed the viral loads and T cell infiltrates in the brains of SIV-infected rhesus monkeys whose CNS function (sensory evoked potential) was impaired. Following infection, CNS evoked potentials were abnormal, indicating early CNS disease. Upon autopsy at 11 wk post-SIV inoculation, the brains of infected animals contained over 5-fold more CD8+ T cells than did uninfected controls. In both infected and uninfected groups, these CD8+ T cells presented distinct levels of activation markers (CD11a and CD95) at different sites: brain > CSF > spleen = blood > lymph nodes. The CD8+ cells obtained from the brains of infected monkeys expressed mRNA for cytolytic and proinflammatory molecules, such as granzymes A and B, perforin, and IFN-γ. Therefore, the neurological dysfunctions correlated with increased numbers of CD8+ T cells of an activated phenotype in the brain, suggesting that virus-host interactions contributed to the related CNS functional defects.

Astrocytes contribute to gamma oscillations and recognition memory

Significance Astrocytes are well placed to modulate neural activity. However, the functions typically attributed to astrocytes are associated with a temporal dimension significantly slower than the timescale of synaptic transmission of neurons. Consequently, it has been assumed that astrocytes do not play a major role in modulating fast neural network dynamics known to underlie cognitive behavior. By creating a transgenic mouse in which vesicular release from astrocytes can be reversibly blocked, we found that astrocytes are necessary for novel object recognition behavior and to maintain functional gamma oscillations both in vitro and in awake-behaving animals. Our findings reveal an unexpected role for astrocytes in neural information processing and cognition. Glial cells are an integral part of functional communication in the brain. Here we show that astrocytes contribute to the fast dynamics of neural circuits that underlie normal cognitive behaviors. In particular, we found that the selective expression of tetanus neurotoxin (TeNT) in astrocytes significantly reduced the duration of carbachol-induced gamma oscillations in hippocampal slices. These data prompted us to develop a novel transgenic mouse model, specifically with inducible tetanus toxin expression in astrocytes. In this in vivo model, we found evidence of a marked decrease in electroencephalographic (EEG) power in the gamma frequency range in awake-behaving mice, whereas neuronal synaptic activity remained intact. The reduction in cortical gamma oscillations was accompanied by impaired behavioral performance in the novel object recognition test, whereas other forms of memory, including working memory and fear conditioning, remained unchanged. These results support a key role for gamma oscillations in recognition memory. Both EEG alterations and behavioral deficits in novel object recognition were reversed by suppression of tetanus toxin expression. These data reveal an unexpected role for astrocytes as essential contributors to information processing and cognitive behavior.

Age-independent and age-related deficits in visuospatial learning, sleep-wake states, thermoregulation and motor activity in PDAPP mice.

Recent studies demonstrated that mice overexpressing the human mutant beta-amyloid precursor protein (hbetaAPP; PDAPP mice) show age-independent and age-related deficits in spatial learning. We used behavioral and electrophysiological techniques to determine in young and aged PDAPP mice whether deficits in spatial learning also involve alterations in sleep-wake states, thermoregulation and motor activity. Consistent with earlier studies, young PDAPP mice exhibited selective age-independent deficits using spatial, but not random and serial strategies in the circular maze. Aged PDAPP mice exhibited deficits using all search strategies. The core body temperature (Tb) in young and aged PDAPP mice was significantly lower than in age-matched non-transgenic (non-Tg) littermates. During the dark period, the motor activity (LMA) was significantly increased in young PDAPP mice, but not in aged PDAPP mice. During the light period, young PDAPP mice showed a reduction in the generation of rapid-eye-movement (REM) sleep. In contrast, aged PDAPP mice exhibited a reduction in the amount of time spent in W and an increase in SWS during the light period. Aged PDAPP mice also showed an increase in the amount of time spent in W and a reduction in REM sleep during the dark period. Our findings support previous reports indicating deficits in spatial learning in young and aged PDAPP mice. These data also suggest that PDAPP mice exhibit age-independent and age-related deficits in neural mechanisms regulating visuospatial learning, the total amount and the circadian distribution of sleep-wake states, thermoregulation and motor activity.

Neuropeptide S Reinstates Cocaine-Seeking Behavior and Increases Locomotor Activity through Corticotropin-Releasing Factor Receptor 1 in Mice

Neuropeptide S (NPS) is a recently discovered neuropeptide that increases arousal and wakefulness while decreasing anxiety-like behavior. Here, we used a self-administration paradigm to demonstrate that intracerebroventricular infusion of NPS reinstates extinguished cocaine-seeking behavior in a dose-dependent manner in mice. The highest dose of NPS (0.45 nm) increased active lever pressing in the absence of cocaine to levels that were equivalent to those observed during self-administration. In addition, we examined the role of the corticotropin-releasing factor receptor 1 (CRF1) in this behavior as well as locomotor stimulation and anxiolysis. CRF1 knock-out mice did not respond to either the locomotor stimulant or cocaine reinstatement effects of NPS, but still responded to its anxiolytic effect. The CRF1 antagonist antalarmin also blocked the increase in active lever responding in the reinstatement model and the locomotor activating properties of NPS without affecting its anxiolytic actions. Our results suggest that NPS receptors may be an important target for drug abuse research and treatment and that CRF1 mediates the cocaine-seeking and locomotor stimulant effects of NPS, but not its effects on anxiety-like behavior.

Effect of Oleamide on Sleep and Its Relationship to Blood Pressure, Body Temperature, and Locomotor Activity in Rats

Oleamide (cis-9,10-octadecenoamide) is a brain lipid that has recently been isolated from the cerebral fluid of sleep-deprived cats. Intracerebroventricular and intraperitoneal administration of oleamide induces sleep in rats. However, it is unclear whether oleamides hypnogenic effects are mediated, in part, by its actions on blood pressure and core body temperature. Here we show that systemic administration of oleamide (10 and 20 mg/kg) in rats increased slow-wave sleep 2, without affecting blood pressure and heart rate. In addition, oleamide decreased body temperature and locomotor activity in a dose-dependent manner. These latter effects were not correlated in time with the observed increases in slow-wave sleep. These data suggest that the hypnogenic effects of oleamide are not related to changes in blood pressure, heart rate, or body temperature.

Urotensin II Modulates Rapid Eye Movement Sleep through Activation of Brainstem Cholinergic Neurons

Urotensin II (UII) is a cyclic neuropeptide with strong vasoconstrictive activity in the peripheral vasculature. UII receptor mRNA is also expressed in the CNS, in particular in cholinergic neurons located in the mesopontine tegmental area, including the pedunculopontine tegmental (PPT) and lateral dorsal tegmental nuclei. This distribution suggests that the UII system is involved in functions regulated by acetylcholine, such as the sleep-wake cycle. Here, we tested the hypothesis that UII influences cholinergic PPT neuron activity and alters rapid eye movement (REM) sleep patterns in rats. Local administration of UII into the PPT nucleus increases REM sleep without inducing changes in the cortical blood flow. Intracerebroventricular injection of UII enhances both REM sleep and wakefulness and reduces slow-wave sleep 2. Intracerebroventricular, but not local, administration of UII increases cortical blood flow. Moreover, whole-cell recordings from rat-brain slices show that UII selectively excites cholinergic PPT neurons via an inward current and membrane depolarization that were accompanied by membrane conductance decreases. This effect does not depend on action potential generation or fast synaptic transmission because it persisted in the presence of TTX and antagonists of ionotropic glutamate, GABA, and glycine receptors. Collectively, these results suggest that UII plays a role in the regulation of REM sleep independently of its cerebrovascular actions by directly activating cholinergic brainstem neurons.

Antiviral treatment normalizes neurophysiological but not movement abnormalities in simian immunodeficiency virus–infected monkeys

Simian immunodeficiency virus (SIV) infection of rhesus monkeys provides an excellent model of the central nervous system (CNS) consequences of HIV infection. To discern the relationship between viral load and abnormalities induced in the CNS by the virus, we infected animals with SIV and later instituted antiviral treatment to lower peripheral viral load. Measurement of sensory-evoked potentials, assessing CNS neuronal circuitry, revealed delayed latencies after infection that could be reversed by lowering viral load. Cessation of treatment led to the reappearance of these abnormalities. In contrast, the decline in general motor activity induced by SIV infection was unaffected by antiviral treatment. An acute increase in the level of the chemokine monocyte chemoattractant protein-1 (MCP-1) was found in the cerebrospinal fluid (CSF) relative to plasma in the infected animals at the peak of acute viremia, likely contributing to an early influx of immune cells into the CNS. Examination of the brains of the infected animals after return of the electrophysiological abnormalities revealed diverse viral and inflammatory findings. Although some of the physiological abnormalities resulting from SIV infection can be at least temporarily reversed by lowering viral load, the viral-host interactions initiated by infection may result in long-lasting changes in CNS-mediated functions.