Differential Fractal and Circadian Patterns in Motor Activity in Spontaneously Hypertensive Rats at the Stage of Prehypertension.

One possible pathological mechanism underlying hypertension and its related health consequences is dysfunction of the circadian system-a network of coupled circadian clocks that generates and orchestrates rhythms of ≈24 h in behavior and physiology. To better understand the role of circadian function during the development of hypertension, circadian regulation of motor activity is investigated in spontaneously hypertensive rats (SHRs) before the onset of hypertension and in their age-matched controls-Wistar Kyoto rats (WKYs). Two complementary properties in locomotor activity fluctuations are examined to assessthe multiscale regulatory function of the circadian control network: 1) rhythmicity at ≈24 h and 2) fractal patterns-similar temporal correlation at different time scales (≈0.5-8 h). Compared to WKYs, SHRs have more stable and less fragmented circadian activity rhythms but the changes in the rhythms (e.g., period and amplitude) from constant dark to light conditions are reduced or opposite. SHRs also have altered fractal activity patterns, displaying activity fluctuations with excessive regularity at small timescales that are linked to rigid physiological states. These different rhythmicity/fractal patterns and their different responses to light in SHRs indicate that an altered circadian function may be involved in the development of hypertension.

Early changes of immunoreactivity to orexin in hypothalamus and to RFamide peptides in brainstem during the development of hypertension.

Baroreflex sensitivity (BRS) is an important function of the nervous system and essential for maintaining blood pressure levels in the physiological range. In hypertension, BRS is decreased both in man and animals. Although increased sympathetic activity is thought to be the main cause of decreased BRS, hence the development of hypertension, the BRS is regulated by both sympathetic (SNS) and parasympathetic (PNS) nervous system. Here, we analyzed neuropeptide changes in the lateral hypothalamus (LH), which favours the SNS activity, as well as in PNS nuclei in the brainstem of spontaneously hypertensive rats (SHR) and their normotensive controls (Wistar Kyoto rats- WKY). The analyses revealed that in the WKY rats the hypothalamic orexin system, known for its role in sympathetic activation, showed a substantial decrease when animals age. At the same time, however, such a decrease was not observed when hypertension developed in the SHR. In contrast, Neuropeptide FF (NPFF) and Prolactin Releasing Peptide (PrRP) expression in the PNS associated Nucleus Tractus Solitarius (NTS) and Dorsal Motor Nucleus of the Vagus (DMV) diminished substantially, not only after the establishment of hypertension but also before its onset. Therefore, the current results indicate early changes in areas of the central nervous system involved in SNS and PNS control of blood pressure and associated with the development of hypertension.

Neuropeptide changes in the suprachiasmatic nucleus are associated with the development of hypertension.

Human postmortem studies as well as experimental animal studies indicate profound changes in neuropeptide expression in the suprachiasmatic nucleus (SCN) in several pathological conditions including hypertension. In addition, animal experimental observations show that the SCN peptides, vasopressin (AVP) and vasoactive intestinal peptide (VIP) are essential for adequate rhythmicity. These data prompted us to investigate whether changes in these neuronal populations could be the cause or consequence of hypertension. Changes in blood pressure and levels of neuropeptide expression in the SCN were determined during development of hypertension in spontaneously hypertensive rats (SHR), in 2K1C reno-vascular induced hypertensive animals and their respective controls. During the pre-hypertensive stage (5 weeks of age), the VIP and AVP content was higher and the somatostatin (SOM) content was lower in the SHR SCN. At the onset of hypertension (12 weeks of age), when blood pressure levels had just reached about 140 mmHg, AVP and SOM content in the SCN was not different anymore in SHRs compared to control, but VIP was still higher. After 16 weeks, the AVP content was decreased, but SOM was increased and the overall level of VIP in the SCN was still higher in SHRs compared to controls. None of the aforementioned changes in the SCN was observed after induction of hypertension in the 2K1C model. However, while VIP was increased in the NTS projecting medial region of the SCN in SHR animals only after the establishment of hypertension, VIP was decreased in the same region in the 2K1C induced hypertensive rats. Consequently, the present findings confirm previous studies in human and rat indicating that changes in the SCN are strongly associated with the development of hypertension. In addition, the changes in peptide content in the 2K1C animals indicate that the SCN is also able to respond to increases in blood pressure.

Functional changes of the SCN in spontaneous hypertension but not after the induction of hypertension.

The present study investigates the circadian behavior of spontaneously hypertensive rats (SHRs) during the pre-hypertensive and hypertensive stage, with the aim to gain insight into whether observed changes in the functionality of suprachiasmatic nucleus (SCN) in the hypertensive state are cause or consequence of hypertension. Four types of animals were used in this study: (1) SHRs which develop hypertension genetically; (2) their normotensive controls, Wistar Kyoto rats (WKYs); (3) Wistar rats whereby hypertension was surgically induced (2 Kidney 1 Clamp (2K1C) method); and (4) sham-operated control Wistar rats. Period length and activity levels and amplitude changes of locomotor and wheel running activity were determined, in constant conditions, as a measure of the functionality of the SCN. Hereto two conditions were used, constant darkness (0 lux) and constant dim (5 lux) light. SHRs showed a shortened period of their locomotor and running wheel activity rhythms in constant darkness during both pre-hypertensive and hypertensive stages and exhibited period lengthening in constant dim light conditions, only during hypertensive stages. Total amount as well as the amplitude of daily running wheel rhythms showed an inverse correlation with the period length, and this relation was significantly different in SHRs compared to WKYs. None of the aforementioned changes in circadian rhythms were observed after the surgical induction of hypertension. The present findings suggest early functional changes of the SCN in the etiology of spontaneous hypertension.

Effect of lesioning the suprachiasmatic nuclei on behavioral despair in rats.

The suprachiasmatic nucleus (SCN) is involved in regulating many biological rhythms. Several lines of research implicate the SCN in affective behavior. The SCN is directly involved in regulating the daily rhythms of the hypothalamo-pituitary-adrenal (HPA) axis hormones involved in stress. Bilateral lesions of the SCN disrupt both the rhythms and the basal levels of the HPA axis hormones involved in coping with stress. Moreover, stress can affect the biological rhythms regulated by the SCN, and disruption of biological rhythms in turn can cause stress. The present study assessed the effect of bilateral destruction of the SCN on behavioral despair, an animal model of depression sensitive to antidepressant treatment. The results indicate that bilateral destruction of the SCN results in reduced immobility in the second forced swimming test (FST) compared to sham controls and animals with incomplete lesions. These results indicate that bilateral destruction of the SCN has a protective effect in the induction of behavioral despair which may arise out of disruption of the secretion of the HPA axis hormones and/or of the neural connections between the SCN and the limbic structures that modulate the response to swim stress.

Central nervous determination of food storage--a daily switch from conservation to expenditure: implications for the metabolic syndrome.

Here, we present a neuroendocrine concept to review the circularly interacting energy homeostasis system between brain and body. Body-brain interaction is circular because the brain immediately integrates an input to an output, and because part of this response may be that the brain modulates the sensitivity of this perception. First, we describe how the brain senses the body through neurons and blood-borne factors. Direct neuronal connections report the state of various organs. In addition, humoral factors are perceived by the blood-brain barrier and circumventricular organs. We describe how circulating energy carriers are sensed and what signals reach the brain during food intake, exercise and an immune response. We describe that the brain regulates the homeostatic process at two fundamentally different levels during the active and inactive states. The unbalanced output of the brain in the metabolic syndrome is discussed in relation with such circadian rhythms and with regional activity of the autonomic nervous system. In line with the above, we suggest a new approach for the diagnosis and therapy of the metabolic syndrome.

A single day of constant light (L/L) provides immunity to behavioral despair in female rats maintained on an L/D cycle.

The present experiment investigated the potentially ameliorative effect of exposure to light in the dark phase of an 12:12 h daily lighting schedule (12L/12D cycle) on behavioral despair, an animal model of depression based on two forced swim tests separated by 24 h. Experimental groups of female Wistar rats were maintained on the 12L/12D cycle except for a single exposure to 12 h of light treatment in the dark phase of the 12L/12D cycle. Control animals were treated similarly except for light treatment. Animals then underwent one of two sets of behavioral tests starting on either the day light (or control) treatment ended (No Delay groups) or 24 h thereafter (Delay groups). The treatment for subgroups of light-treated and control animals tested with or without delay consisted of either two forced swim tests separated by 24 h or testing in the open field and elevated plus maze. Results indicated that a single exposure to a 12-h light treatment has protective effect on behavioral despair in groups tested with or without delay as measured by shorter duration of immobility in the second swim test compared to the controls. Light-treated and control animals behaved similarly in the open field and elevated plus-maze tests.