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Rats are believed to communicate their emotional state by emitting two distinct types of ultrasonic vocalizations. The first is long “22-kHz” vocalizations (>300 ms, 32 kHz), often frequency-modulated, in appetitive situations. Here we are first to describe a new-type of aversive vocalizations emitted at a higher pitch by Wistar and spontaneously hypertensive rats (SHR) in an intensified aversive state – prolonged fear conditioning. These calls, which we named “44-kHz vocalizations”, are long (>150 ms), generally at a constant frequency (usually within 35-50 kHz range) and have an overall spectrographic image similar to 22-kHz calls. Some 44-kHz vocalizations are comprised of both 22-kHz-like and 44-kHz-like elements. Furthermore, two separate clustering methods confirmed that these 44-kHz calls are distinct from other vocalizations. We also show that some of rats’ responses to the playback of 44-kHz calls were more akin to that of aversive calls, e.g. heart rate changes, whereas other responses were at an intermediate level between aversive and appetitive calls. Our results suggest that rats have a wider vocal repertoire than previously believed, and current definitions of major call types may require reevaluation.

Many symptoms used routinely for human psychiatric diagnosis cannot be directly observed in animals which cannot describe their internal states. However, the ultrasonic vocalizations (USV) rodents use to communicate their emotional states can be measured. USV have therefore become a particularly useful tool in brain disease models. Spontaneously hypertensive rats (SHR) are considered an animal model of attention deficit hyperactivity disorder (ADHD) and schizophrenia. However, the specifics of SHR's behavior have not been fully described and there is very little data on their USV. Recently, we developed a communication model, in which Wistar rats are exposed to pre-recorded playbacks of aversive (22-kHz) or appetitive (50-kHz) USV, and their vocal responses depend on the extent of prior fear conditioning (0, 1, 6 or 10 shocks). Here, we investigated SHR's behavior and heart rate (HR) in our communication model, in comparison to Wistar rats employed as controls. In general, SHR emitted typical USV categories, however, they contained more short 22-kHz and less 50-kHz USV overall. Moreover, fewer SHR, in comparison with Wistar rats, emitted long 22-kHz USV after fear conditioning. SHR did not show a 50-kHz playback-induced HR increase, while they showed a profound 22-kHz playback-induced HR decrease. Finally, the number of previously delivered conditioning shocks appeared to have no effect on the investigated vocal, locomotor and HR responses of SHR. The phenomena observed in SHR are potentially attributable to deficits in emotional perception and processing. A lower number of 50-kHz USV emitted by SHR may reflect observations of speech impairments in human patients and further supports the usefulness of SHR to model ADHD and schizophrenia.

We found previously that intravenous kynurenic acid (KYNA), a native broad spectrum glutamate antagonist, increases renal blood flow and induces natriuresis in anesthetized spontaneously hypertensive rats (SHR). Since such changes may affect systemic circulation and can potentially find therapeutic application, in this study we examined long term influence of orally administered KYNA on systemic and renal hemodynamics and renal excretion in conscious SHR. KYNA was administered in drinking water at a dose of 25 mg/kg/day for 3 weeks. Heart rate (HR), systolic (SBP), and mean arterial pressure (MAP) were measured through telemetry. The records were taken at the beginning of the study (control, day 0), and then on day 7, 14, and 21 of treatment. Diuresis (V), total solute excretion (UosmV), and sodium excretion (UNaV) were determined on days 0, 7, and 14. KYNA consistently decreased HR, from 319 ± 8 to 291 ± 5, 299 ± 9 and 284 ± 6 beats/min on day 7, 14, and 21, respectively, (− 9, − 6, and − 11%; p

The contribution of chymase, one of the enzymes responsible for angiotensin II generation in non-ACE pathway, remains unclear in the development of hypertension. The aim of the study was to investigate chymase inhibition as potential antihypertensive therapy in spontaneously hypertensive rats (SHR). To block chymase we employed chymostatin, a commercial inhibitor, and new analogues of rapeseed-derived peptides, VWIS and RIY. These simple and easy to obtain peptides not only block chymase, but also possess weak activity to inhibit ACE. This is a first attempt to evaluate the impact of chronic administration of selected inhibitors on blood pressure of SHR in two phases of hypertension. Male SHR (6 or 16 weeks old) were treated daily for two weeks with chymostatin (CH; 2 mg/kg/day), the peptides VWIS (12.5 mg/kg/day) or RIY (7.5 mg/kg/day); control groups received chymostatin solvent (0.15% DMSO in saline) or peptide solvent (saline). The substances were administered intravenously to conscious animals via a chronically cannulated femoral vein. Systolic blood pressure (SBP) was measured by telemetry. Metabolic parameters were measured weekly, and tissue samples were harvested after two weeks of treatment. None of the administered chymase inhibitors affected the development of hypertension in young rats. Only RIY exhibited beneficial properties when administered in the established phase of hypertension: SBP decreased from 165 ± 10 to 157 ± 7 mmHg while the excretion of nitric oxide metabolites increased significantly. The glomerulosclerosis index was lower after RIY treatment in both age groups (significant only in young rats 0.29 ± 0.05 vs 0.48 ± 0.04 in the control group; p < 0.05). Hence, it seems that peptide RIY exhibits some positive effect on renal morphology. The results obtained suggest that the peptide RIY may be a useful tool in the treatment of hypertension, especially in cases when ACE inhibitors are not effective.

Major depressive disorder is a complex disease resulting from aberrant synaptic plasticity that may be caused by abnormal serotonergic signaling. Using a combination of behavioral, biochemical, and imaging methods, we analyze 5-HT7R/MMP-9 signaling and dendritic spine plasticity in the hippocampus in mice treated with the selective 5-HT7R agonist (LP-211) and in a model of chronic unpredictable stress (CUS)-induced depressive-like behavior. We show that acute 5-HT7R activation induces depressive-like behavior in mice in an MMP-9-dependent manner and that post mortem brain samples from human individuals with depression reveal increased MMP-9 enzymatic activity in the hippocampus. Both pharmacological activation of 5-HT7R and modulation of its downstream effectors as a result of CUS lead to dendritic spine elongation and decreased spine density in this region. Overall, the 5-HT7R/MMP-9 pathway is specifically activated in the CA1 subregion of the hippocampus during chronic stress and is crucial for inducing depressive-like behavior.

Spatial chromatin organization is crucial for transcriptional regulation and might therefore be particularly dynamic in neurons since these terminally differentiated cells dramatically change their transcriptome in response to external stimuli. Here, we show that stimulation of neurons causes condensation of large chromatin domains. We find that this phenomenon is not only induced in rat hippocampal neurons cultured in vitro, but is also present in vivo in amygdala neurons of rats subjected to fear conditioning, and hippocampal neurons of animals subjected to kainate evoked seizures or High-Frequency Stimulation (HFS). The activity-induced chromatin condensation is an active, very rapid, and reversible process, that is independent of transcription and precedes the expression of Immediate Early Genes (IEG). It is accompanied by the redistribution of posttranslational modifications of histones, and rearrangements in the spatial organization of chromosome territories. Moreover, it leads to the reorganization of nuclear speckles and active domains located in their proximity. Finally, we find that neurons depleted of the histone deacetylase HDAC1 fail to condense chromatin upon stimulation, a phenomenon that can be fully reversed by the introduction of human HDAC1. Taken together, our results suggest that the HDAC1-dependent chromatin reorganization might constitute an important level of fine-tuning of transcriptional regulation in stimulated neurons.

Summary Our rudimentary knowledge about rat intraspecific vocal system of information exchange is limited by experimental models of communication. Rats emit 50-kHz ultrasonic vocalizations in appetitive states and 22-kHz ones in aversive states. Both affective states influence heart rate. We propose a behavioral model employing exposure to pre-recorded playbacks in home-cage-like conditions. Fifty-kHz playbacks elicited the most vocalizations (>60 calls per minute, mostly of 50-kHz type), increased heart rate, and locomotor activity. In contrast, 22-kHz playback led to abrupt decrease in heart rate and locomotor activity. Observed effects were more pronounced in singly housed rats compared with the paired housed group; they were stronger when evoked by natural playback than by corresponding artificial tones. Finally, we also observed correlations between the number of vocalizations, heart rate levels, and locomotor activity. The correlations were especially strong in response to 50-kHz playback., Graphical Abstract, Highlights • Rats vocalized abundantly when exposed to recorded ultrasonic playback • Playback of appetitive calls caused an increase in heart rate • Playback of alarm/aversive calls caused a decrease in heart rate • Singly housed rats exhibited more vocalizations and higher heart rate, Biological Sciences; Animals; Ethology

The course and outcome of multiple diseases is worsened by high salt intake, often but not always via elevation of arterial blood pressure. Excessive salt consumption increases the incidence of cardiovascular disorders, including myocardial infarction, heart failure or stroke, also of chronic kidney disease and diabetes. More than 30% of the Western populations is affected by arterial hypertension, and “prehypertension” is diagnosed in a similar percentage of subjects; these people will become hypertensive within a couple of years. Unfortunately, the pathomechanisms of hypertension remain largely unclear; emphasized is the role of arterial stiffening and kidney glomerular injury. Recent literature of the subject indicates an urgent need for reduction of worldwide salt consumption and it agrees that this would substantially reduce mortality in cardiovascular disease and also help alleviate progression of many diseases like heart failure, chronic kidney disease, and diabetes.

Background/Aims. High salt (HS) intake may elevate blood pressure (BP), also in animals without genetic salt sensitivity. The development of salt-dependent hypertension could be mediated by endogenous vasoactive agents; here we examined the role of vasodilator epoxyeicosatrienoic acids (EETs) and vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Methods. In conscious Wistar rats on HS diet systolic BP (SBP) was examined after chronic elevation of EETs using 4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB), a blocker of soluble epoxide hydrolase, or after inhibition of 20-HETE with 1-aminobenzotriazole (ABT). Thereafter, in acute experiments the responses of renal artery blood flow (Transonic probe) and renal regional perfusion (laser-Doppler) to intrarenal acetylcholine (ACh) or norepinephrine were determined. Results. HS diet increased urinary 20-HETE excretion. The SBP increase was not reduced by c-AUCB but prevented by ABT until day 5 of HS exposure. Renal vasomotor responses to ACh or norepinephrine were similar on standard and HS diet. ABT but not c-AUCB abolished the responses to ACh. Conclusions. 20-HETE seems to mediate the early-phase HS diet-induced BP increase while EETs are not engaged in the process. Since HS exposure did not alter renal vasodilator responses to Ach, endothelial dysfunction is not a critical factor in the mechanism of salt-induced blood pressure elevation.

Potential toxicity of a cationic derivative of polyprenol (APren-7) with lipofecting activity was examined, especially its influence on renal haemodynamics and function, in order to conduct further investigation of its suitability as a component of liposomal drug carriers. Sprague–Dawley rats received daily injections (0.5 mL, s.c.) of liposomes comprised of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and APren-7 (LP); classic liposomes composed of DOPE only (L); water solvent (W). After 4 weeks rats were anaesthetised and a wide spectrum of functional parameters were measured. These included mean arterial blood pressure (MBP), total renal blood flow (RBF), renal cortical, outer and inner medullary blood flow (CBF, OMBF, IMBF, respectively), diuresis, and sodium and solute excretion. Most parameters did not significantly differ between treated and control groups. A lower OMBF/IMBF ratio in liposome-treated groups (L: 1.0 ± 0.1; LP: 1.1 ± 0.1 vs. W: 1.9 ± 0.3, p

Novel lipid-based carriers, composed of cationic derivatives of polyisoprenoid alcohols (amino-prenols, APrens) and 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE), were designed. The carriers, which were previously shown to be nontoxic to living organisms, were now tested if suitable for administration of candesartan, an antihypertensive drug. Spontaneously hypertensive rats (SHR) received injections of candesartan (0.1 mg/kg body weight per day; s.c.) in freshly prepared carriers for two weeks. The rats’ arterial pressure was measured by telemetry. Urine and blood collection were performed in metabolic cages. In a separate group of SHR, the pharmacokinetics of the new formulation was evaluated after a single subcutaneous injection. The antihypertensive activity of candesartan administered in DOPE dispersions containing APrens was distinctly greater than that of candesartan dispersions composed of DOPE only or administered in the classic solvent (sodium carbonate). The pharmacokinetic parameters clearly demonstrated that candesartan in APren carriers reached the bloodstream more rapidly and in much greater concentration (almost throughout the whole observation) than the same drug administered in dispersions of DOPE only or in solvent. Serum creatinine (PCr) decreased significantly only in the group receiving candesartan in carriers with APrens (from 0.80 ± 0.04 to 0.66 ± 0.09 mg/dl; p

Opioids interact with sympathetic and renin–angiotensin systems in control of mean arterial pressure (MAP). Our earlier finding that biphalin, a synthetic enkephalin analogue, decreased MAP in anaesthetized spontaneously hypertensive rats (SHR) prompted us to further explore this action, to get new insights into pathogenesis of various forms of hypertension. Biphalin effects were studied in SHR, uninephrectomized rats on a high-salt diet (HS/UNX), and rats with angiotensin-induced hypertension (Ang-iH). Besides MAP, renal and iliac blood flows (RBF, IBF) and vascular resistances were measured. In anaesthetized and conscious SHR, biphalin (300 μg·h−1·kg−1i.v.) decreased MAP by ∼10 and ∼20 mm Hg, respectively (P < 0.001). In anaesthetized HS/UNX and normotensive rats, MAP increased by ∼6–7 mm Hg (P < 0.02); without anaesthesia, only transient decreases occurred. MAP never changed in Ang-iH rats. Morphine (1.5 mg·h−1·kg−1i.v.) decreased MAP in HS/UNX but only transiently so without anaesthesia; such anaesthesia dependence of response was also seen in normotensive rats. Ang-iH rats never responded to morphine. Hypotensive effect in SHR only depends primarily on the reduction by biphalin of vascular responsiveness to increased sympathetic stimulation; such increase is well documented for SHR. No MAP response to biphalin or morphine in Ang-iH could depend on angiotensin-induced alterations of the vascular wall morphology and function.

Aim: Interaction was examined of nitric oxide (NO) and cytochrome P-450 (CYP-450)-dependent arachidonic acid derivatives, 20-HETE and EETs, in control of arterial pressure (MABP) and renal function. Modification of this interaction by changing sodium intake was also studied. Methods: On low, standard or high Na diet (LS, STD and HS rats respectively) effects of sequential blockade of NO synthases (NOS) and CYP-450 enzyme activity on MABP, renal blood flow (RBF, Transonic probe), renal medullary perfusion (MBF, laser-Doppler technique), medullary tissue NO (selective electrode) and renal excretion were examined in anaesthetized rats. All NOS were blocked with Nϖ-nitro-l-arginine methyl ester (l-NAME), the neuronal NOS with S-methyl-l-thiocitrulline (SMTC), and CYP-450 with 1-aminobenzotriazole (ABT). Results: In each diet group the baseline MABP was highest in rats pre-treated with l-NAME. CYP-450 inhibition significantly decreased MABP only in LS (−9%) and HS rats (−22%) pre-treated with l-NAME. This MABP decrease correlated directly with the dietary sodium content (r = 0.644, P