The Interaction of Vasopressin with Hormones of the Hypothalamo-Pituitary-Adrenal Axis: The Significance for Therapeutic Strategies in Cardiovascular and Metabolic Diseases.

A large body of evidence indicates that vasopressin (AVP) and steroid hormones are frequently secreted together and closely cooperate in the regulation of blood pressure, metabolism, water-electrolyte balance, and behavior, thereby securing survival and the comfort of life. Vasopressin cooperates with hormones of the hypothalamo-pituitary-adrenal axis (HPA) at several levels through regulation of the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and multiple steroid hormones, as well as through interactions with steroids in the target organs. These interactions are facilitated by positive and negative feedback between specific components of the HPA. Altogether, AVP and the HPA cooperate closely as a coordinated functional AVP-HPA system. It has been shown that cooperation between AVP and steroid hormones may be affected by cellular stress combined with hypoxia, and by metabolic, cardiovascular, and respiratory disorders; neurogenic stress; and inflammation. Growing evidence indicates that central and peripheral interactions between AVP and steroid hormones are reprogrammed in cardiovascular and metabolic diseases and that these rearrangements exert either beneficial or harmful effects. The present review highlights specific mechanisms of the interactions between AVP and steroids at cellular and systemic levels and analyses the consequences of the inappropriate cooperation of various components of the AVP-HPA system for the pathogenesis of cardiovascular and metabolic diseases.

Neurophysiology of male sexual arousal-Behavioral perspective.

In the presented review, we analyzed the physiology of male sexual arousal and its relation to the motivational aspects of this behavior. We highlighted the distinction between these processes based on observable physiological and behavioral parameters. Thus, we proposed the experimentally applicable differentiation between sexual arousal (SA) and sexual motivation (SM). We propose to define sexual arousal as an overall autonomic nervous system response leading to penile erection, triggered selectively by specific sexual cues. These autonomic processes include both spinal and supraspinal neuronal networks, activated by sensory pathways including information from sexual partner and sexual context, as well as external and internal genital organs. To avoid misinterpretation of experimental data, we also propose to precise the term "sexual motivation" as all actions performed by the individual that increase the probability of sexual interactions or increase the probability of exposition to sexual context cues. Neuronal structures such as the amygdala, bed nucleus of stria terminalis, hypothalamus, nucleus raphe, periaqueductal gray, and nucleus paragigantocellularis play crucial roles in controlling the level of arousal and regulating peripheral responses via specific autonomic effectors. On the highest level of CNS, the activity of cortical structures involved in the regulation of the autonomic nervous system, such as the insula and anterior cingulate cortex, can visualize an elevated level of SA in both animal and human brains. From a preclinical perspective, we underlie the usefulness of the non-contact erection test (NCE) procedure in understanding factors influencing sexual arousal, including studies of sexual preference in animal models. Taken together results obtained by different methods, we wanted to focus attention on neurophysiological aspects that are distinctly related to sexual arousal and can be used as an objective parameter, leading to higher translational transparency between basic, preclinical, and clinical studies.

A Protocol for the Non-invasive Method of Ultrasound Separation During the Sociosexual Vocal-Non-contact Model in Rats.

Ultrasonic vocalization (USV) is one of the measurable behavioral parameters of sociosexual interactions in rats. To precisely and accurately describe the neurobehavioral properties of USV and the potentially related specific emotional responsiveness of animals, we need to know which animals vocalize and what is their exact behavioral and physiological response. To this end, we modified the non-contact cage [non-contact erection model (NCE)] by adding a modification [vocalization-non-contact erection (VOC-NCE)] that makes it possible to assign emitted ultrasonic signals to a particular animal. Typically, the NCE cage consists of two compartments separated by perforated baffles. A male is placed in one section, and a receptive female is placed in the other section. This makes possible the accurate description of sexual parameters related to the cues controlled by the experimenter. In VOC-NCE, we completely separated the male USV from the female USV by three appropriately perforated baffles and located microphones combined with ultrasonic screening. We recorded emission in both typical bands, the so-called 22- and 50-kHz bands, with various subtypes, thus highlighting the utility of our protocol to investigate the sexual dimorphism of vocalization. Similar to the anticipatory model, we showed that emission can occur without acoustic feedback from concomitants during the VOC-NCE test. Therefore, we propose a relatively simple method for assigning individual vocalization. We discuss its usefulness and limitations in assessing vocal differentiation related to sexual parameters, adaptive changes during conditioning procedures, and further applications.

Gender differences in short- vs. long-term impact of maternal depression following pre-gestational chronic mild stress.

Major Depressive Disorder (MDD) with Peripartum Onset was classified in 2013 by the Diagnostic and Statistical Manual, Fifth Edition (DMS-5) and approved in 2019 by the World Health Organization (WHO). These diagnostic revisions call for the development of new animal models of maternal depression, emphasizing the pregnancy period. We have recently described a novel rat model of maternal MDD with a Peripartum Onset. Exposure to pre-gestational chronic mild stress (CMS) with repeated restrain resulted in maternal depressive-like behavior and impacted offspring's neurodevelopment. The present study examined gender differences in short- vs. long-term neurodevelopmental impact of pre-gestational maternal stress. Stress response was assessed in Sprague Dawley CMS-exposed dams (n=7) by metabolic, hormonal, and behavioral changes and compared to controls dams (n=7). Short-term impact of maternal stress on offspring was examined in terms of metabolic, neurodevelopmental, and behavioral tests in male (n=40) and female (n=35) adolescent offspring on a postnatal day (PD) 48; the long-term impact was assessed in adult male (n=13) and female (n=12) offspring on PD 225. Brain tissue was collected from adolescent and adult offspring for biochemical analysis. Maternal stress was associated with decreased body weight and increased urinary corticosterone during the pre-pregnancy period, but depressive-like behavior was delayed until later in pregnancy. No significant neurodevelopmental changes in suckling male or female offspring derived from the stress-exposed dams were observed. However, adolescent male and female offspring of stress-exposed dams displayed an increased depressive-like behavior and gender-dependent increase in anxiety-like behavior in female offspring. These changes were associated with a brain-region-specific increase in brain-derived neurotrophic factor (BDNF) protein and BDNF receptor (TrkB) mRNA in males. Behavioral changes observed in the adolescents receded in adult male and female offspring. However, plasma BDNF was elevated in stress-exposed adult female offspring. These results suggest that pre-gestational maternal stress is associated with gender-dependent short- vs. long-term neurodevelopmental impact in the offspring. Presented data are of significant public health relevance, and there is an urgent need for further research to confirm these findings and probe the underlying mechanisms.

Anticipatory 50-kHz Precontact Ultrasonic Vocalizations and Sexual Motivation: Characteristic Pattern of Ultrasound Subtypes in an Individual Analyzed Profile.

We verified the hypothesis of the existence of forms of individual-specific differences in the emission of anticipatory precontact vocalization (PVs) indicating individualization related to sexual experience and motivation in male rats. Long-Evans males were individually placed in a chamber and 50-kHz ultrasounds were recorded during 5-min periods. In experiment 1, PVs were recorded before the introduction of a female in four consecutive sessions during the acquisition of sexual experience. In experiment 2, PVs were analyzed in three groups of sexually experienced males: with the highest, moderate, and the lowest sexual motivation based on previous copulatory activity. In both experiments, the total number of ultrasounds, as well as 14 different specific subtypes, was measured. The ultrasound profiles for each male were created by analyzing the proportions of specific dominant subtypes of so-called 50-kHz calls. We decided that the dominant ultrasounds were those that represented more than 10% of the total recorded signals in a particular session. The number of PVs was positively correlated with the acquisition of sexual experience and previous copulatory efficiency (measured as the number of sessions with ejaculation). Furthermore, PVs showed domination of the frequency modulated signals (complex and composite) as well as flat and short with upward ramp ultrasounds with some individual differences, regardless of the level of sexual motivation. The results show a characteristic pattern of PVs and confirm the hypothesis that the number of PVs is a parameter reflecting the level of sexual motivation.

Distinct classes of low frequency ultrasonic vocalizations in rats during sexual interactions relate to different emotional states.

This study examined low-frequency ultrasonic vocalizations (lUSVs) in rats during two types of sexual interactions; postejaculatory interval (PEI) and barrier - noncontact (NC) test. We report distinct classes of lUSVs that can be assigned to different emotional states; relaxation vs. frustration. Totally flat, 22-kHz calls (Class A), were observed during the relaxation state following ejaculation; characterized by immobilization or grooming during the PEI. On the other hand, two-three component lUSVs (Class B) that start at a higher frequency (45-kHz: flat, upward or short signal) and then shift to 35-23-kHz (mostly to 28-23-kHz), correspond as we assume, to arousal and frustration - active states associated with sniffing a hole or exploration during the NC test. We suggest that momentary, abrupt decreases of arousal during the frustration state correspond to Class B lUSVs. The detailed spectral analysis of the high-frequency component of two-component lUSVs is crucial for establishing the relationship between such lUSVs and the corresponding behavior and emotional states. Our studies indicate that while the two-component Class B 22-kHz lUSVs may relate to the frustration state, a single component, flat, Class A lUSV relates to the relaxation state. The results of these studies support a notion that rats emit distinct vocalization patterns, reflecting their emotional states.

The Sexual Motivation of Male Rats as a Tool in Animal Models of Human Health Disorders.

Normal or dysfunctional sexual behavior seems to be an important indicator of health or disease. Many health disorders in male patients affect sexual activity by directly causing erectile dysfunction, affecting sexual motivation, or both. Clinical evidence indicates that many diseases strongly disrupt sexual motivation and sexual performance in patients with depression, addiction, diabetes mellitus and other metabolic disturbances with obesity and diet-related factors, kidney and liver failure, circadian rhythm disorders, sleep disturbances including obstructive sleep apnea syndrome, developmental and hormonal disorders, brain damages, cardiovascular diseases, and peripheral neuropathies. Preclinical studies of these conditions often require appropriate experimental paradigms, including animal models. Male sexual behavior and motivation have been intensively investigated over the last 80 years in animal rat model. Sexual motivation can be examined using such parameters as: anticipatory behavior and 50-kHz ultrasonic vocalizations reflecting the emotional state of rats, initiation of copulation, efficiency of copulation, or techniques of classical (pavlovian) and instrumental conditioning. In this review article, we analyze the behavioral parameters that describe the sexual motivation and sexual performance of male rats in the context of animal experimental models of human health disorders. Based on analysis of the parameters describing the heterogeneous and complex structure of sexual behavior in laboratory rodents, we propose an approach that is useful for delineating distinct mechanisms affecting sexual motivation and sexual performance in selected disease states and the efficacy of therapy in preclinical investigations.

Modulation of 22-khz postejaculatory vocalizations by conditioning to new place: Evidence for expression of a positive emotional state.

It has been assumed that the 22-kHz ultrasonic vocalizations (USVs) are emitted by adult rats as a result of a negative emotional state. However, emission of the 22-kHz vocalizations by male rats has been also observed following ejaculation, which has a high rewarding value as shown by a conditioned place preference test. These observations suggest that 22-kHz USVs may also occur in response to a positive emotional state. The aim of this study was to determine whether the postejaculatory 22-kHz USVs are related to conditioning processes. The 22 kHz USVs were recorded in Sprague-Dawley males in the postejaculatory refractory period during conditioning processes to a new chamber unrelated to copulation. During the first session in the clean recording chamber, males vocalized marginally and exhibited intensive rearing behavior. From the second to fourth sessions, vocalization duration increased and the number of rearing decreased. Following established conditioning process, odor cues from foreign males, but not the familiar ones, resulted in decreased duration of 22-kHz USVs and increased the number of rearing. On the other hand, in the presence of mating cues (copulatory chamber and presence of the female), males exhibited increased duration of postejaculatory 22-kHz USVs and reduced number of rearing. These results demonstrated that the conditioning to the cues, both unrelated and related to copulation, is important for evoking postejaculatory 22-kHz USVs as well as the relaxation state. Furthermore, these results confirmed the postejaculatory 22-kHz USVs' involvement in expression of the positive emotional state. (PsycINFO Database Record