Orexinergic neuron susceptibility to neuroinflammatory and aging-related neurodegenerative diseases

Orexins (a.k.a. hypocretins) play a crucial role in several physiological functions, including energy balance and the maintenance of wakefulness. Deficient orexin signalling is the hallmark of the sleep disorder narcolepsy. Although immune mechanisms have been hypotesized, the pathogenesis of narcolepsy remains to be clarified. Less attention has been devoted to potential orexinergic system alterations in other conditions, and their potential relationships with inflammatory signalling. Neuroinflammation has raised increasing interest in recent years, not only in relation to typical neuroinflammatory diseases, but also with regard to aging-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. A role for neuroinflammatory signalling in normal, “healthy” aging is also currently debated, since several lines of evidence have pointed to aging as a chronic low-grade proinflammatory condition. We have examined neurons in the lateral hypothalamus expressing orexin A in different paradigms: i) normal aging in mice, ii) rodent models of a chronic infectious neuroinflammatory condition represented by a parasitic disease that causes sleep/wake alterations, iii) PDAAP mutant mice, a model of Alzheimer’s disease. In these paradigms, we have identified different degrees of neuronal loss in the orexinergic cell population and/or evidence of functional dysregulation of these neurons, together with glial activation in the lateral hypothalamus and sleep/wake changes. Altogether, the data point to a vulnerability of orexin to inflammatory signalling, and potentially place the neuropeptide at the center of neural-immune interactions, drawing attention on the relationships between neuroinflammation, sleep regulation, and orexin neuron damage

Expression of interferon-inducible chemokines and sleep/wake changes during early encephalitis in experimental African trypanosomiasis

Background: Human African trypanosomiasis or sleeping sickness, caused by the parasite Trypanosoma brucei, leads to neuroinflammation and characteristic sleep/wake alterations. The relationship between the onset of these alterations and the development of neuroinflammation is of high translational relevance, but remains unclear. This study investigates the expression of interferon (IFN)-γ and IFN-inducible chemokine genes in the brain, and the levels of CXCL10 in the serum and cerebrospinal fluid prior to and during the encephalitic stage of trypanosome infection, and correlates these with sleep/wake changes in a rat model of the disease. Methodology/Principal findings: The expression of genes encoding IFN-γ, CXCL9, CXCL10, and CXCL11 was assessed in the brain of rats infected with Trypanosoma brucei brucei and matched controls using semi-quantitative end-point RT-PCR. Levels of CXCL10 in the serum and cerebrospinal fluid were determined using ELISA. Sleep/wake states were monitored by telemetric recording. Using immunohistochemistry, parasites were found in the brain parenchyma at 14 days post-infection (dpi), but not at 6 dpi. Ifn-γ, Cxcl9, Cxcl10 and Cxcl11 mRNA levels showed moderate upregulation by 14 dpi followed by further increase between 14 and 21 dpi. CXCL10 concentration in the cerebrospinal fluid increased between 14 and 21 dpi, preceded by a rise in the serum CXCL10 level between 6 and 14 dpi. Sleep/wake pattern fragmentation was evident at 14 dpi, especially in the phase of wake predominance, with intrusion of sleep episodes into wakefulness. Conclusions/Significance: The results show a modest increase in Cxcl9 and Cxcl11 transcripts in the brain and the emergence of sleep/wake cycle fragmentation in the initial encephalitic stage, followed by increases in Ifn-γ and IFN-dependent chemokine transcripts in the brain and of CXCL10 in the cerebrospinal fluid. The latter parameter and sleep/wake alterations could provide combined humoral and functional biomarkers of the early encephalitic stage in African trypanosomiasis

Experimental sleep deprivation as a tool to test memory deficits in rodents.

Paradigms of sleep deprivation (SD) and memory testing in rodents (laboratory rats and mice) are here reviewed. The vast majority of these studies have been aimed at understanding the contribution of sleep to cognition, and in particular to memory. Relatively little attention, instead, has been devoted to SD as a challenge to induce a transient memory impairment, and therefore as a tool to test cognitive enhancers in drug discovery. Studies that have accurately described methodological aspects of the SD protocol are first reviewed, followed by procedures to investigate SD-induced impairment of learning and memory consolidation in order to propose SD protocols that could be employed as cognitive challenge. Thus, a platform of knowledge is provided for laboratory protocols that could be used to assess the efficacy of drugs designed to improve memory performance in rodents, including rodent models of neurodegenerative diseases that cause cognitive deficits, and Alzheimer's disease in particular. Issues in the interpretation of such preclinical data and their predictive value for clinical translation are also discussed

The aging brain, neuroinflammatory signaling and sleep-wake regulation

Tissues and organs change over time, regulated by intrinsic (genetic) determinants and environmental (and microenvironmental) adaptation. Brain changes during lifetime are especially critical, as the brain is the effector of cognition and the vast majority of neurons live throughout the life of the individual. In addition, brain aging mechanisms are especially critical for disease vulnerability, given the aging­related prevalence of pathologies that include neurodegenerative diseases. In this context, the present contribution concisely highlights data yielded by recent trends of research on the normal aging brain, and specifically: the occurrence of synaptic changes (rather than neuronal loss) and the altered regulation of adult neurogenesis (which represents a novel exciting field of knowledge); the development of a low­grade chronic inflammatory state which primes glial cells and may lead to changes in intercellular crosstalk, thus playing a potential role in the brain susceptibility to neurodegeneration; changes occurring in state­dependent behavior, sleep and wake, which are products of global brain functioning and underlie consciousness and cognitive performance; changes in the biological clock, the hypothalamic suprachiasmatic nucleus, which regulates sleep­wake alternation and other endogenous rhythms. Altogether, the present synopsis of recent studies at the molecular, cellular, and functional levels emphasizes the idea that the normal aging brain should be viewed as an example of adaptation and plasticity rather than as an obligatory decline

Neonatal treatment with clomipramine induces morphological and cellular changes in the adult rat brain

Clomipramine (CLI) is a tricyclic serotonin reuptake blocker, widely used to treat depression, obsessive compulsive disorder (OCD), and other psychiatric conditions in human patients. Chronic CLI administration in the neonate rodent alters serotonergic circuits and serotonine levels in the brain, and has been reported to cause a complex pattern of behavioral changes in the adult life, including abnormalities of rapid eye movement sleep, decreased aggression and sexual behavior, anhaedonia and helplessness. Such symptoms suggest a parallel with humans endogenous depression and have been proposed as a novel animal model of OCD. The present study was aimed at identifying morphological and cellular changes after chronic neonatal treatment with clomipramine (daily i.p. injections, 20 mg/kg, from P5 to P21) in the brain of 5 month-old male Sprague-Dawley rats, compared to saline-treated littermates, using three distinct experimental approaches. 1) In vivo volumetric analyses based on structural MRI scans performed at 4.7T on 6 CLI-treated and 6 control rats revealed a significant reduction in total brain and hippocampal volume, as well as enlarged ventricles in CLI-treated rats, compared to saline-treated cohorts. 2) In order to investigate treatment-related developmental disorders, we studied the dendritic arborization of newly generated cells in the hippocampus of 7 CLI and 7 control rats. Two-dimensional dendritic tracing diagrams were reconstructed with Neurolucida, and quantitative analyses of total dendritic length and arborization indices in the two groups are still ongoing. 3) Brain-derived neurotrophic factor (BDNF) levels were assessed in the hippocampus and neocortex of 5 CLI and 5 control rats by ELISA assay. Interestingly, we found significant region-specific, between-group differences. In particular, BDNF levels, important for neurogenesis, differentiation and neuronal survival, and highly expressed in brain areas involved in cognitive and emotional behavior, were significantly decreased in the hippocampus of CLI rats compared to controls, whereas no differences were found in the cortex. Taken together, the data suggest that interfering with serotonergic regulation during early postnatal development can produce permanent brain changes. These resemble brain abnormalities repeatedly observed not only in human depression but also in schizophrenia. Further morphological analyses as well as experiments aimed at characterizing the behavioral correlates of early CLI administration are in progress

The deployment of visual attention in time: evidence from normal observers and brain-damaged patients

Non disponibileThe study of the Attentional blink phenomenon has revealed to be one of the most useful tool to get insights abount the temporal constraints that limit rapid shifts in attentional redeployment. We report the interesting finding that, both in normal observers and, to some extent, also in brain-damaged patients, the magnitude of the interference effect described in the Attentional Blink can be reduced by the concomitant presentation of a task-irrelevant auditory stimulation which is able to induce a better temporal segmentation of the visual sequence. this argues against the unavoidable nature of the Attentional Blink effect, suggesting that rather than a fundamental limitation of attentional selection in time, it could be considered as a failure in optimally organize a flux of rapid and brief events

Limbic thalamus and state-dependent behavior: the paraventricular nucleus of the thalamic midline as a node in circadian timing and sleep/wake-regulatory networks.

The paraventricular thalamic nucleus (PVT), the main component of the dorsal thalamic midline, receives multiple inputs from the brain stem and hypothalamus, and targets the medial prefrontal cortex, nucleus accumbens and amygdala. PVT has been implicated in several functions, especially adaptation to chronic stress, addiction behaviors and reward, mood, emotion. We here focus on the wiring and neuronal properties linking PVT with circadian timing and sleep/wake regulation, and their behavioral implications. PVT is interconnected with the master circadian pacemaker, the hypothalamic suprachiasmatic nucleus, receives direct and indirect photic input, is densely innervated by orexinergic neurons which play a key role in arousal and state transitions. Endowed with prominent wake-related Fos expression which is suppressed by sleep, and with intrinsic neuronal properties showing a diurnal oscillation unique in the thalamus, PVT could represent a station of interaction of thalamic and hypothalamic sleep/wake-regulatory mechanisms. PVT could thus play a strategic task by funneling into limbic and limbic-related targets circadian timing and state-dependent behavior information, tailoring it for cognitive performance and motivated behaviors

Sleep and rhythm changes at the time of Trypanosoma brucei invasion of the brain parenchyma in the rat.

Human African trypanosomiasis (HAT), or sleeping sickness, is a severe disease caused by Trypanosoma brucei (T.b.). The disease hallmark is sleep alterations. Brain involvement in HAT is a crucial pathogenetic step for disease diagnosis and therapy. In this study, a rat model of African trypanosomiasis was used to assess changes of sleep-wake, rest-activity, and body temperature rhythms in the time window previously shown as crucial for brain parenchyma invasion by T.b. to determine potential biomarkers of this event. Chronic radiotelemetric monitoring in Sprague-Dawley rats was used to continuously record electroencephalogram, electromyogram, rest-activity, and body temperature in the same animals before (baseline recording) and after infection. Rats were infected with T.b. brucei. Data were acquired from 1 to 20 d after infection (parasite neuroinvasion initiates at 11-13 d post-infection in this model), and were compared to baseline values. Sleep parameters were manually scored from electroencephalographic-electromyographic tracings. Circadian rhythms of sleep time, slow-wave activity, rest-activity, and body temperature were studied using cosinor rhythmometry. Results revealed alterations of most of the analyzed parameters. In particular, sleep pattern and sleep-wake organization plus rest-activity and body temperature rhythms exhibited early quantitative and qualitative alterations, which became marked around the time interval crucial for parasite neuroinvasion or shortly after. Data derived from actigrams showed close correspondence with those from hypnograms, suggesting that rest-activity could be useful to monitor sleep-wake alterations in African trypanosomiasis