Daniel Carneiro Carrettiero

TRPV4 activates autonomic and behavioural warmth‐defence responses in Wistar rats

In this study, we aimed at investigating the involvement of the warmth‐sensitive channel – TRPV4 (in vitro sensitive to temperatures in the range of approx. 24–34 °C) – on the thermoregulatory mechanisms in rats.

Current understanding on the neurophysiology of behavioral thermoregulation

Temperature influence on the physiology and biochemistry of living organisms has long been recognized, which propels research in the field of thermoregulation. With the cloning and characterization of the transient receptor potential (TRP) ion channels as the principal temperature sensors of the mammalian somatosensory neurons, the understanding, at a molecular level, of thermosensory and thermoregulatory mechanisms became promising. Because thermal environment can be extremely hostile (temperature range on earths surface is from ∼ −69°C to 58°C), living organisms developed an array of thermoregulatory strategies to guarantee survival, which include both autonomic mechanisms, which aim at increasing or decreasing heat exchange between body, and ambient and behavioral strategies. The knowledge regarding neural mechanisms involved in autonomic thermoregulatory strategies has progressed immensely compared to the knowledge on behavioral thermoregulation. This review aims at collecting the up-to-date knowledge on the neural basis for behavioral thermoregulation in mammals in order to point out perspectives and deployment of this research field.

Temperature and toxic Tau in Alzheimer's disease: new insights

Alzheimers disease (AD), the most common dementia in the elderly, is characterized by cognitive impairment and severe autonomic symptoms such as disturbance in core body temperature (Tc), which may be predictors or early events in AD onset. Inclusions of phosphorylated Tau (p-Tau) are a hallmark of AD and other neurodegenerative disorders called “Tauopathies.” Animal and human studies show that anesthesia augments p-Tau levels through reduction of Tc, with implications for AD. Additionally, hypothermia impairs memory and cognitive function. The molecular networks related to Tc that are associated with AD remain poorly characterized. Under physiological conditions, Tau binds microtubules, promoting their assembly and stability. The dynamically regulated Tau-microtubule interaction plays an important role in structural remodeling of the cytoskeleton, having important functions in neuronal plasticity and memory in the hippocampus. Hypothermia-induced increases in p-Tau levels are significant, with an 80% increase for each degree Celsius below normothermic conditions. Although the effects of temperature on Tau phosphorylation are evident, its effects on p-Tau degradation remain poorly understoodWe review information concerning the mechanisms of Tau regulation of neuron plasticity via its effects on microtubule dynamics, with focus on pathways regulating the abundance of phosphorylated Tau species. We highlight the effects of temperature on molecular mechanisms influencing the development of Tau-related diseases. Specifically, we argue that cold might preferentially affects central nervous system structures that are highly reliant upon plasticity, such as the hippocampus, and that the effect of cold on Tau phosphorylation may constitute a pathology-initiating trigger leading to neurodegeneration.

BAG2 expression dictates a functional intracellular switch between the p38-dependent effects of nicotine on tau phosphorylation levels via the α7 nicotinic receptor

The histopathological hallmarks present in Alzheimers disease (AD) brain are plaques of Aβ peptide, neurofibrillary tangles of hyperphosphorylated tau protein, and a reduction in nicotinic acetylcholine receptor (nAChR) levels. The role of nAChRs in AD is particularly controversial. Tau protein function is regulated by phosphorylation, and its hyperphosphorylated forms are significantly more abundant in AD brain. Little is known about the relationship between nAChR and phospho-tau degradation machinery. Activation of nAChRs has been reported to increase and decrease tau phosphorylation levels, and the mechanisms responsible for this discrepancy are not presently understood. The co-chaperone BAG2 is capable of regulating phospho-tau levels via protein degradation. In SH-SY5Y cell line and rat primary hippocampal cell culture low endogenous BAG2 levels constitute an intracellular environment conducive to nicotine-induced accumulation of phosphorylated tau protein. Further, nicotine treatment inhibited endogenous expression of BAG2, resulting in increased levels of phosphorylated tau indistinguishable from those induced by BAG2 knockdown. Conversely, overexpression of BAG2 is conducive to a nicotine-induced reduction in cellular levels of phosphorylated tau protein. In both cases the effect of nicotine was p38MAPK-dependent, while the α7 antagonist MLA was synthetic to nicotine treatment, either increasing levels of phospho-Tau in the absence of BAG2, or further decreasing the levels of phospho-Tau in the presence of BAG2. Taken together, these findings reconcile the apparently contradictory effects of nicotine on tau phosphorylation by suggesting a role for BAG2 as an important regulator of p38-dependent tau kinase activity and phospho-tau degradation in response to nicotinic receptor stimulation. Thus, we report that BAG2 expression dictates a functional intracellular switch between the p38-dependent functions of nicotine on tau phosphorylation levels via the α7 nicotinic receptor.

BAG2 Is Repressed by NF-κB Signaling, and Its Overexpression Is Sufficient to Shift Aβ1-42 from Neurotrophic to Neurotoxic in Undifferentiated SH-SY5Y Neuroblastoma

Amyloid-beta (Aβ) binds to various neuronal receptors and elicits a context- and dose-dependent toxic or trophic response from neurons. The molecular mechanisms for this phenomenon are presently unknown. The cochaperone BAG2 has been shown to mediate important cellular responses to stress, including cell cycle arrest and apoptosis. Here, we use SH-SY5Y neuroblastoma cells to characterize BAG2 expression and regulation and investigate the involvement of BAG2 in Aβ1-42-mediated neurotrophism or neurotoxicity in the context of differentiation. We report that BAG2 is upregulated on differentiation of SH-SY5Y cells into neuron-like cells. This increase in BAG2 expression is accompanied by a change in response to treatment with Aβ1-42 from neurotrophic to neurotoxic. Further, overexpression of BAG2 in undifferentiated SH-SY5Y cells was sufficient to induce the change from neurotrophic to neurotoxic response. Of several transcription factors queried, the putative BAG2 promoter had a higher-than-expected occurrence of response elements (RE) for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Treatment with JSH-23, a potent inhibitor of NF-κB, caused a marked increase in BAG2 mRNA expression, suggesting that NF-κB is a repressor of BAG2 transcription in undifferentiated SH-SY5Y cells. Together, these data suggest that NF-κB-mediated modulation of BAG2 expression constitutes a “switch” that regulates the shift between the neurotrophic and neurotoxic effects of Aβ1-42.

Alpha2-adrenoceptor and adenosine A1 receptor within the nucleus tractus solitarii in hypertension development

Alpha2-adrenoceptor and A1 adenosine receptor systems within the nucleus tractus solitarii (NTS) play an important role in cardiovascular control. Deregulation of these systems may result in an elevated sympathetic tone, one of the root causes of neurogenic hypertension. The dorsomedial/dorsolateral and subpostremal NTS subnuclei of spontaneously hypertensive rats (SHR) show density changes in both receptors, even at 15 days of age, prior to the onset of hypertension. In addition, adenosine A1 receptors have been specifically reported to modulate alpha2-adrenoceptors in several brain regions, including the NTS, via a PLC-dependent pathway involving cross regulation between sympathetic neurons and astrocytes. The physiological cross talk between these receptor systems is also deregulated in SHR suggesting that alpha2-adrenoceptor and A1 adenosine receptor might be germane to the development of hypertension. In this review, we will focus on these systems within the NTS during development, pointing out some interesting modulations in processes, and chemical changes within specific subnuclei of NTS circuitry, that might have implications for neurogenic hypertension.

Defining Multivariate Normative Rules for Healthy Aging using Neuroimaging and Machine Learning: An Application to Alzheimer's Disease

BACKGROUND Neuroimaging techniques combined with computational neuroanatomy have been playing a role in the investigation of healthy aging and Alzheimers disease (AD). The definition of normative rules for brain features is a crucial step to establish typical and atypical aging trajectories. OBJECTIVE To introduce an unsupervised pattern recognition method; to define multivariate normative rules of neuroanatomical measures; and to propose a brain abnormality index. METHODS This study was based on a machine learning approach (one class classification or novelty detection) to neuroanatomical measures (brain regions, volume, and cortical thickness) extracted from the Alzheimers Disease Neuroimaging Initiative (ADNI)s database. We applied a ν-One-Class Support Vector Machine (ν-OC-SVM) trained with data from healthy subjects to build an abnormality index, which was compared with subjects diagnosed with mild cognitive impairment and AD. RESULTS The method was able to classify AD subjects as outliers with an accuracy of 84.3% at a false alarm rate of 32.5%. The proposed brain abnormality index was found to be significantly associated with group diagnosis, clinical data, biomarkers, and future conversion to AD. CONCLUSION These results suggest that one-class classification may be a promising approach to help in the detection of disease conditions. Our findings support a framework considering the continuum of brain abnormalities from healthy aging to AD, which is correlated with cognitive impairment and biomarkers measurements.

Thermoregulatory profile of neurodegeneration-induced dementia of the Alzheimer's type using intracerebroventricular streptozotocin in rats

Here, we have extensively investigated the relationship between thermoregulation and neurodegeneration‐induced dementia of the Alzheimers type using intracerebroventricular injections of streptozotocin (icv‐STZ).

Short-term menthol treatment promotes persistent thermogenesis without induction of compensatory food consumption in Wistar rats: implications for obesity control

In this study, we aimed to evaluate the influence of daily repeated menthol treatments on body mass and thermoregulatory effectors in Wistar rats, considering that menthol is a transient receptor potential melastatin 8 channel agonist that mimics cold sensation and activates thermoregulatory cold-defense mechanisms in mammals, promoting hyperthermia and increasing energy expenditure, and has been suggested as an anti-obesity drug. Male Wistar rats were topically treated with 5% menthol for 3 or 9 consecutive days while body mass, food intake, abdominal temperature, metabolism, cutaneous vasoconstriction, and thermal preference were measured. Menthol promoted hyperthermia on all days of treatment, due to an increase in metabolism and cutaneous vasoconstriction, without affecting food intake, resulting in less mass gain in menthol-hyperthermic animals. As the treatment progressed, the menthol-induced increases in metabolism and hyperthermia were attenuated but not abolished. Moreover, cutaneous vasoconstriction was potentiated, and an increase in the warmth-seeking behavior was induced. Taken together, the results suggest that, although changes occur in thermoeffector recruitment during the course of short-term treatment, menthol is a promising drug to prevent body mass gain. NEW & NOTEWORTHY Menthol produces a persistent increase in energy expenditure, with limited compensatory thermoregulatory adaptations and, most unexpectedly, without affecting food intake. Thus short-term treatment with menthol results in less mass gain in treated animals compared with controls. Our results suggest that menthol is a promising drug for the prevention of obesity.

Hypercapnic and Hypoxic Respiratory Response During Wakefulness and Sleep in a Streptozotocin Model of Alzheimer’s Disease in Rats

Besides the typical cognitive decline, patients with Alzheimers disease (AD) develop disorders of the respiratory system, such as sleep apnea, shortness of breath, and arrhythmias. These symptoms are aggravated with the progression of the disease. However, the cause and nature of these disturbances are not well understood. Here, we treated animals with intracerebroventricular streptozotocin (STZ, 2 mg/kg), a drug that has been described to cause Alzheimer-like behavioral and histopathological impairments. We measured ventilation (V̇E), electroencephalography, and electromyography during normocapnia, hypercapnia, and hypoxia in Wistar rats. In addition, we performed western blot analyses for phosphorylated tau, total tau, and amyloid-β (Aβ) peptide in the locus coeruleus (LC), retrotrapezoid nucleus, medullary raphe, pre-Bötzinger/Bötzinger complex, and hippocampus, and evaluated memory and learning acquisition using the Barnes maze. STZ treatment promoted memory and learning deficits and increased the percentage of total wakefulness during normocapnia and hypercapnia due to a reduction in the length of episodes of wakefulness. CO2-drive to breathe during wakefulness was increased by 26% in STZ-treated rats due to an enhanced tidal volume, but no changes in V̇E were observed in room air or hypoxic conditions. The STZ group also showed a 70% increase of Aβ in the LC and no change in tau protein phosphorylation. In addition, no alteration in body temperature was observed. Our findings suggest that AD animals present an increased sensitivity to CO2 during wakefulness, enhanced Aβ in the LC, and sleep disruption.