Adult Male Mice Emit Context-Specific Ultrasonic Vocalizations That Are Modulated by Prior Isolation or Group Rearing Environment

Social interactions in mice are frequently analysed in genetically modified strains in order to get insight of disorders affecting social interactions such as autism spectrum disorders. Different types of social interactions have been described, mostly between females and pups, and between adult males and females. However, we recently showed that social interactions between adult males could also encompass cognitive and motivational features. During social interactions, rodents emit ultrasonic vocalizations (USVs), but it remains unknown if call types are differently used depending of the context and if they are correlated with motivational state. Here, we recorded the calls of adult C57BL/6J male mice in various behavioral conditions, such as social interaction, novelty exploration and restraint stress. We introduced a modulator for the motivational state by comparing males maintained in isolation and males maintained in groups before the experiments. Male mice uttered USVs in all social and non-social situations, and even in a stressful restraint context. They nevertheless emitted the most important number of calls with the largest diversity of call types in social interactions, particularly when showing a high motivation for social contact. For mice maintained in social isolation, the number of calls recorded was positively correlated with the duration of social contacts, and most calls were uttered during contacts between the two mice. This correlation was not observed in mice maintained in groups. These results open the way for a deeper understanding and characterization of acoustic signals associated with social interactions. They can also help evaluating the role of motivational states in the emission of acoustic signals

Gestational Valproate Alters BOLD Activation in Response to Complex Social and Primary Sensory Stimuli

Valproic acid (VPA) has been used clinically as an anticonvulsant medication during pregnancy; however, it poses a neurodevelopmental risk due to its high teratogenicity. We hypothesized that midgestational (GD) exposure to VPA will lead to lasting deficits in social behavior and the processing of social stimuli. To test this, animals were given a single IP injection of 600 mg/kg of VPA on GD 12.5. Starting on postnatal day 2 (PND2), animals were examined for physical and behavior abnormalities. Functional MRI studies were carried out after PND60. VPA and control animals were given vehicle or a central infusion of a V1a antagonist 90 minutes before imaging. During imaging sessions, rats were presented with a juvenile test male followed by a primary visual stimulus (2 Hz pulsed light) to examine the effects of prenatal VPA on neural processing. VPA rats showed greater increases in BOLD signal response to the social stimulus compared to controls in the temporal cortex, thalamus, midbrain and the hypothalamus. Blocking the V1a receptor reduced the BOLD response in VPA animals only. Neural responses to the visual stimulus, however, were lower in VPA animals. Blockade with the V1a antagonist did not revert this latter effect. Our data suggest that prenatal VPA affects the processing of social stimuli and perhaps social memory, partly through a mechanism that may involve vasopressin V1a neurotransmission

Beaming into the Rat World: Enabling Real-Time Interaction between Rat and Human Each at Their Own Scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human’s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale

Dopaminergic modulation of affective and social deficits induced by prenatal glucocorticoid exposure

Prenatal stress or exposure to elevated levels of glucocorticoids (GCs) can impair specific neurobehavioral circuits leading to alterations in emotional processes later in life. In turn, emotional deficits may interfere with the quality and degree of social interaction. Here, by using a comprehensive behavioral approach in combination with the measurement of ultrasonic vocalizations, we show that in utero GC (iuGC)-exposed animals present increased immobility in the forced swimming test, pronounced anhedonic behavior (both anticipatory and consummatory), and an impairment in social interaction at different life stages. Importantly, we also found that social behavioral expression is highly dependent on the affective status of the partner. A profound reduction in mesolimbic dopaminergic transmission was found in iuGC animals, suggesting a key role for dopamine (DA) in the etiology of the observed behavioral deficits. Confirming this idea, we present evidence that a simple pharmacological approach—acute L-3,4-dihydroxyphenylacetic acid (L-DOPA) oral administration, is able to normalize DA levels in iuGC animals, with a concomitant amelioration of several dimensions of the emotional and social behaviors. Interestingly, L-DOPA effects in control individuals were not so straightforward; suggesting that both hypo- and hyperdopaminergia are detrimental in the context of such complex behaviors.This work was supported by a grant of Institute for the Study of Affective Neuroscience (ISAN) and Janssen Neurosciences Prize. SB and AJR have Fundacao para a Ciencia e Tecnologia (FCT) fellowships (SFRH/BD/89936/2012; SFRH/BPD/33611/2009)

Communication calls produced by electrical stimulation of four structures in the guinea pig brain

One of the main central processes affecting the cortical representation of conspecific vocalizations is the collateral output from the extended motor system for call generation. Before starting to study this interaction we sought to compare the characteristics of calls produced by stimulating four different parts of the brain in guinea pigs (Cavia porcellus). By using anaesthetised animals we were able to reposition electrodes without distressing the animals. Trains of 100 electrical pulses were used to stimulate the midbrain periaqueductal grey (PAG), hypothalamus, amygdala, and anterior cingulate cortex (ACC). Each structure produced a similar range of calls, but in significantly different proportions. Two of the spontaneous calls (chirrup and purr) were never produced by electrical stimulation and although we identified versions of chutter, durr and tooth chatter, they differed significantly from our natural call templates. However, we were routinely able to elicit seven other identifiable calls. All seven calls were produced both during the 1.6 s period of stimulation and subsequently in a period which could last for more than a minute. A single stimulation site could produce four or five different calls, but the amygdala was much less likely to produce a scream, whistle or rising whistle than any of the other structures. These three high-frequency calls were more likely to be produced by females than males. There were also differences in the timing of the call production with the amygdala primarily producing calls during the electrical stimulation and the hypothalamus mainly producing calls after the electrical stimulation. For all four structures a significantly higher stimulation current was required in males than females. We conclude that all four structures can be stimulated to produce fictive vocalizations that should be useful in studying the relationship between the vocal motor system and cortical sensory representation

Chlamydia trachomatis Infection and Anti-Hsp60 Immunity: The Two Sides of the Coin

Chlamydia trachomatis (CT) infection is one of the most common causes of reproductive tract diseases and infertility. CT-Hsp60 is synthesized during infection and is released in the bloodstream. As a consequence, immune cells will produce anti-CT-Hsp60 antibodies. Hsp60, a ubiquitous and evolutionarily conserved chaperonin, is normally sequestered inside the cell, particularly into mitochondria. However, upon cell stress, as well as during carcinogenesis, the chaperonin becomes exposed on the cell surface (sf-Hsp60) and/or is secreted from cells into the extracellular space and circulation. Reports in the literature on circulating Hsp and anti-Hsp antibodies are in many cases short on details about Hsp60 concentrations, and about the specificity spectra of the antibodies, their titers, and their true, direct, pathogenetic effects. Thus, more studies are still needed to obtain a definitive picture on these matters. Nevertheless, the information already available indicates that the concurrence of persistent CT infection and appearance of sf-Hsp60 can promote an autoimmune aggression towards stressed cells and the development of diseases such as autoimmune arthritis, multiple sclerosis, atherosclerosis, vasculitis, diabetes, and thyroiditis, among others. At the same time, immunocomplexes composed of anti-CT-Hsp60 antibodies and circulating Hsp60 (both CT and human) may form deposits in several anatomical locations, e.g., at the glomerular basal membrane. The opposite side of the coin is that pre-tumor and tumor cells with sf-Hsp60 can be destroyed with participation of the anti-Hsp60 antibody, thus stopping cancer progression before it is even noticed by the patient or physician

P2 receptors are involved in the mediation of motivation-related behavior

The importance of purinergic signaling in the intact mesolimbic–mesocortical circuit of the brain of freely moving rats is reviewed. In the rat, an endogenous ADP/ATPergic tone reinforces the release of dopamine from the axon terminals in the nucleus accumbens as well as from the somatodendritic region of these neurons in the ventral tegmental area, as well as the release of glutamate, probably via P2Y1 receptor stimulation. Similar mechanisms may regulate the release of glutamate in both areas of the brain. Dopamine and glutamate determine in concert the activity of the accumbal GABAergic, medium-size spiny neurons thought to act as an interface between the limbic cortex and the extrapyramidal motor system. These neurons project to the pallidal and mesencephalic areas, thereby mediating the behavioral reaction of the animal in response to a motivation-related stimulus. There is evidence that extracellular ADP/ATP promotes goal-directed behavior, e.g., intention and feeding, via dopamine, probably via P2Y1 receptor stimulation. Accumbal P2 receptor-mediated glutamatergic mechanisms seem to counteract the dopaminergic effects on behavior. Furthermore, adaptive changes of motivation-related behavior, e.g., by chronic succession of starvation and feeding or by repeated amphetamine administration, are accompanied by changes in the expression of the P2Y1 receptor, thought to modulate the sensitivity of the animal to respond to certain stimuli

Ultrasonic vocalization in rats self-administering heroin and cocaine in different settings: evidence of substance-specific interactions between drug and setting

Rationale Clinical and preclinical evidence indicates that the setting of drug use affects drug reward in a substance-specific manner. Heroin and cocaine co-abusers, for example, indicated distinct settings for the two drugs: heroin being used preferentially at home and cocaine preferentially outside the home. Similar results were obtained in rats that were given the opportunity to self-administer intravenously both heroin and cocaine. Objectives The goal of the present study was to investigate the possibility that the positive affective state induced by cocaine is enhanced when the drug is taken at home relative to a non-home environment, and vice versa for heroin. Methods To test this hypothesis, we trained male rats to self-administer both heroin and cocaine on alternate days and simultaneously recorded the emission of ultrasonic vocalizations (USVs), as it has been reported that rats emit 50-kHz USVs when exposed to rewarding stimuli, suggesting that these USVs reflect positive affective states. Results We found that Non-Resident rats emitted more 50-kHz USVs when they self-administered cocaine than when self-administered heroin whereas Resident rats emitted more 50-kHz USVs when self-administering heroin than when self-administering cocaine. Differences in USVs in Non-Resident rats were more pronounced during the first self-administration (SA) session, when the SA chambers were completely novel to them. In contrast, the differences in USVs in Resident rats were more pronounced during the last SA sessions. Conclusion These findings indicate that the setting of drug taking exerts a substance-specific influence on the ability of drugs to induce positive affective states