Brief maternal interaction increases number, amplitude, and bout size of isolation-induced ultrasonic vocalizations in infant rats (Rattus norvegicus)

The number, amplitude, duration, and bout structure of isolation-induced ultrasonic vocalization (USV) of infant rats (Rattus norvegicus) were measured on postnatal Day 10. Measurements were made before and after a brief, 1-min, active interaction with their mother or before and after a "pick-up" control procedure. Consistent with prior studies, the number of USVs emitted was significantly increased in the period following the maternal reunion but not after the control procedure. The average amplitude of USVs was also greater following maternal reunion. Finally, analyses characterizing the bout structure of USV production indicated that the average bout size (i.e. number of USVs/bout) was increased severalfold following the reunion with the mother, accounting for the greater rate of USV production during the second isolation period.     

Juvenile stress potentiates aversive 22-kHz ultrasonic vocalizations and freezing during auditory fear conditioning in adult male rats

Traumatic experiences that occur during adolescence can render individuals vulnerable to mood and anxiety disorders. A model in juvenile rats (age: 27-29 days) was developed previously to study the long-term effects of adolescent stress exposure on behaviour and physiology. This paradigm, termed juvenile stress, involves subjecting juvenile rats to different stressors on consecutive days over a 3-day period. Here, we investigated the effects of the juvenile stress paradigm on freezing behaviour and aversive 22-kHz ultrasonic vocalizations (USVs) during auditory fear conditioning in adult male rats (age: 68-90 days). We found that rats previously subjected to juvenile stress increased aversive 22-kHz USVs (total calls and time spent calling) compared with controls during fear-conditioning training. The acoustic USV parameters between control and juvenile stress rats were largely equivalent, including duration, peak frequency and amplitude. While rats did not differ in freezing behaviour during fear conditioning, juvenile stress rats exhibited greater cue-conditioned freezing upon testing 24 h later. Our results show that juvenile stress elicited different long-term changes in freezing and aversive USVs during fear conditioning. Furthermore, they highlight the importance of assessing USVs to detect experience-dependent differences between control and stress-exposed animals which are not detectable by measuring visible behaviour.     

Differential effects of a 5-HT2 receptor blocker on alcohol intake in rats selectively bred for high and low catecholamine responses to stress

The effect of the selective 5-HT2 receptor blocker ritanserin on alcohol consumption was investigated in two strains of rats selectively bred for high and low catecholamine responses to stress. Rats were forced to drink a 5% alcohol solution for 10 days. For the subsequent six days, animals were injected subcutaneously with 2.5 mg/kg/2 ml ritanserin or vehicle only, and both a 5% solution of alcohol and water were presented to the animals. Ritanserin affected neither water nor total fluid intake. Furthermore, no effect of ritanserin on alcohol consumption could be demonstrated in high-responding rats, whereas in low-responding rats a very pronounced ritanserin-induced reduction in alcohol intake was observed. Results are discussed in terms of mediating effects of serotonergic neurons on mesolimbic dopaminergic reward systems related to drug addiction.     

Asymmetrical stimulus generalization following differential fear conditioning

Rodent ultrasonic vocalizations (USVs) are ethologically critical social signals. Rats emit 22 kHz USVs and 50 kHz USVs, respectively, in conjunction with negative and positive affective states. Little is known about what controls emotional reactivity to these social signals. Using male Sprague–Dawley rats, we examined unconditional and conditional freezing behavior in response to the following auditory stimuli: three 22 kHz USVs, a discontinuous tone whose frequency and on–off pattern matched one of the USVs, a continuous tone with the same or lower frequencies, a 4 kHz discontinuous tone with an on–off pattern matched to one of the USVs, and a 50 kHz USV. There were no differences among these stimuli in terms of the unconditional elicitation of freezing behavior. Thus, the stimuli were equally neutral before conditioning. During differential fear conditioning, one of these stimuli (the CS⁺) always co-terminated with a footshock unconditional stimulus (US) and another stimulus (the CS⁻) was explicitly unpaired with the US. There were no significant differences among these cues in CS⁺-elicited freezing behavior. Thus, the stimuli were equally salient or effective as cues in supporting fear conditioning. When the CS⁺ was a 22 kHz USV or a similar stimulus, rats discriminated based on the principal frequency and/or the temporal pattern of the stimulus. However, when these same stimuli served as the CS⁻, discrimination failed due to generalization from the CS⁺. Thus, the stimuli differed markedly in the specificity of conditioning. This strikingly asymmetrical stimulus generalization is a novel bias in discrimination.     

Testing social acoustic memory in rats: Effects of stimulus configuration and long-term memory on the induction of social approach behavior by appetitive 50-kHz ultrasonic vocalizations

Rats emit distinct types of ultrasonic vocalizations (USVs), which serve as situation-dependent affective signals. In appetitive situations, such as rough-and-tumble-play, high-frequency 50-kHz USVs occur, whereas low-frequency 22-kHz USVs can be observed in aversive situations, such as social defeat. USVs serve distinct communicative functions and induce call-specific behavioral responses in the receiver. While aversive 22-kHz USVs serve as alarm calls and induce behavioral inhibition, appetitive 50-kHz USVs have a pro-social communicative function and elicit social approach behavior, supporting the notion that they serve as social contact calls to (re)establish or maintain contact among conspecifics. The aim of the present study was to use the rat's ability to communicate in the ultrasonic range via high-frequency 50-kHz USVs in order to develop a test for social acoustic memory in rats with relevance for human verbal memory. Verbal learning and memory is among the seven cognitive domains identified as commonly deficient in human schizophrenia patients, but particularly difficult to model. We therefore tested whether the induction of social approach behavior by playback of appetitive 50-kHz USVs is dependent on (1) acoustic stimulus configuration and (2) social long-term memory, and whether (3) social long-term memory effects can be blocked by the administration of scopolamine, a muscarinic acetylcholine antagonist producing amnesia. Results show that social approach behavior in response to playback of natural 50-kHz USVs depends on acoustic stimulus configuration and occurs only when sound energy is concentrated to a critical frequency band in the ultrasonic range. Social approach behavior was detected during the first exposure to playback of 50-kHz USVs, whereas no such response was observed during the second exposure 1week later, indicating a stable memory trace. In contrast, when memory formation was blocked by i.p. administration of scopolamine (0.5mg/kg or 1.5mg/kg) immediately after the first exposure, rats displayed social approach behavior during the second exposure as well. Induction of social approach behavior in response to repeated playback of natural 50-kHz USVs may therefore provide a new and rather unique approach for testing social acoustic memory in rats with relevance to human verbal memory.     

A comparative study of rodent ultrasonic vocalizations during copulation

The temporal patterning of ultrasonic vocalizations (USVs) during copulation was recorded for male-female pairs of Djungarian hamsters (Phodopus campbelli), prairie voles (Microtus ochrogaster), and montane voles (Microtus montanus). Each species appears to utilize a single major frequency band for USVs, centered around 31 kHz for the vole species and 71 kHz for hamsters. Djungarian hamsters exhibited low rates of USVs prior to introduction of the female and following ejaculation, but a high USV rate during periods of copulatory activity. Both vole species called at high rates during all stages of the copulatory sequence, although calling rates decreased following ejaculation. Anesthetization trials, where one pair member was awake and the other anesthesized, suggest that it is the male of each species that produces most USVs. The results were compared with six other muroid species for which data on the temporal patterning of USVs during copulation are available. These data extend our knowledge of the patterning of USVs during copulatory behavior and suggest the need for additional comparative investigations.     

Ritanserin and voluntary alcohol intake in rats

In a previous study (Rammsayer & Vogel, 1991), rats selectively bred for high and low catecholamine responses to stress showed a selective response to the 5-HT2 receptor blocker ritanserin. However, it remained unclear whether selective breeding resulted in a decrease in 5-HT responsivity, as suggested by the lack of an effect in high stress responding rats, or in an increase in 5-HT responsivity, as suggested by ritanserin-induced reduction in alcohol intake in low-responding rats. To answer this question, nonselectively bred rats were forced to drink a 5% alcohol solution for 10 days. For the subsequent six days, animals were injected subcutaneously with 2.5 mg/kg/2 ml ritanserin or vehicle only, and both a 5% solution of alcohol and water were presented to the animals. Ritanserin neither affected alcohol nor total fluid intake suggesting that in the general population of N/NIH (Hansen) rats as well as in rats of the same strain selectively bred for high catecholamine responses, mesolimbic dopaminergic activity is not effectively modulated by specific blockade of 5-HT2 receptors. However, a very pronounced ritanserin induced difference in daily water intake between nonbred male and female rats became evident.     

Mouse vocal communication system: Are ultrasounds learned or innate?

Mouse ultrasonic vocalizations (USVs) are often used as behavioral readouts of internal states, to measure effects of social and pharmacological manipulations, and for behavioral phenotyping of mouse models for neuropsychiatric and neurodegenerative disorders. However, little is known about the neurobiological mechanisms of rodent USV production. Here we discuss the available data to assess whether male mouse song behavior and the supporting brain circuits resemble those of known vocal non-learning or vocal learning species. Recent neurobiology studies have demonstrated that the mouse USV brain system includes motor cortex and striatal regions, and that the vocal motor cortex sends a direct sparse projection to the brainstem vocal motor nucleus ambiguous, a projection previously thought be unique to humans among mammals. Recent behavioral studies have reported opposing conclusions on mouse vocal plasticity, including vocal ontogeny changes in USVs over early development that might not be explained by innate maturation processes, evidence for and against a role for auditory feedback in developing and maintaining normal mouse USVs, and evidence for and against limited vocal imitation of song pitch. To reconcile these findings, we suggest that the trait of vocal learning may not be dichotomous but encompass a broad spectrum of behavioral and neural traits we call the continuum hypothesis, and that mice possess some of the traits associated with a capacity for limited vocal learning.     

If waking and dreaming consciousness became de-differentiated, would schizophrenia result?

If both waking and dreaming consciousness are functional, their de-differentiation would be doubly detrimental. Differentiation between waking and dreaming is achieved through neuromodulation. During dreaming, without external sensory data and with mesolimbic dopaminergic input, hyper-cholinergic input almost totally suppresses the aminergic system. During waking, with sensory gates open, aminergic modulation inhibits cholinergic and mesocortical dopaminergic suppresses mesolimbic. These neuromodulatory systems are reciprocally interactive and self-organizing. As a consequence of neuromodulatory reciprocity, phenomenologically, the self and the world that appear during dreaming differ from those that emerge during waking. As a result of self-organizing, the self and the world in both states are integrated.Some loss of self-organization would precipitate a degree of de-differentiation between waking and dreaming, resulting in a hybrid state which would be expressed heterogeneously, both neurobiologically and phenomenologically. As a consequence of progressive de-differentiation, certain identifiable psychiatric disorders may emerge. Ultimately, schizophrenia, a disorganized-fragmented self, may result.     

Neural substrates of latent inhibition: the switching model

Latent inhibition (LI) refers to decrement in conditioning to a stimulus as a result of its prior nonreinforced preexposure. It is a robust phenomenon that has been demonstrated in a variety of classical and instrumental conditioning procedures and in many mammalian species, including humans. The development of LI is considered to reflect decreased associability of, or attention to, stimuli that predict no significant outcome. The fact that LI is considered to be a reflection of attentional processes has become of increasing importance to neuroscientists who see LI as a convenient tool for measuring the effects of drug treatments and lesions on attention. The present article surveys the data on brain systems, which have been studied in regard to their involvement in LI. These are reviewed and discussed separately in sections on noradrenergic, cholinergic, dopaminergic, serotonergic, and septo-hippocampal manipulations. On the basis of these data, it is concluded that the neural substrates of LI include the mesolimbic dopaminergic system, the mesolimbic serotonergic system, and the hippocampus. It is proposed that the preexposed stimulus loses its capacity to affect behavior in conditioning, even though it predicts reinforcement, because the hippocampus inhibits the switching mechanism of the nucleus accumbens via the subiculum-accumbens pathway. This action of the hippocampus is modulated by the mesolimbic serotonergic system via its interactions with the hippocampal or mesolimbic dopaminergic systems, or both.     

The possibility of pharmacologic therapy of extrapyramidal hyperkineses with tiapride

A novel substance, tiaprid (Tiapridex), from the family of the substituted benzamides, can be used in an attempt to block the dopaminergic receptors of the corpus striatum without inducing the psychiatric side effects on the mesolimbic system associated with, for instance, neuroleptics. Since hyperkinetic illness of the brain-stem ganglions accompanied by myoclonia, athetosis and dystonia are believed to stem from a state of imbalance between dopaminergic and cholinergic processes in which dopaminergic activity predominates, the application of tiaprid was tested on patients with etiologically different illnesses in an open clinical study. The course of treatment was documented by measurements and a record of clinical findings. No tolerance problems were encountered, and the substance had no grave side effects. Its effects proved to be good to very good on myoclonic hyperkinesis and good to moderate on athetosis, but dystonia seemed to be resistant to this form of treatment.     

Examining neurochemical determinants of inspection time: Development of a biological model

Inspection time (IT), an information-processing correlate of psychometric intelligence, has been extensively studied. Previous research has shown that IT is a reliable correlate of psychometric intelligence across different developmental periods, mirroring developmental trends of fluid intelligence. Despite this extensive previous literature, very little is known about the biological basis of IT. In the present review, we discuss recent results from our laboratories examining the neurochemical determinants of IT. In this review, we outline the significance of several studies in which performance on the IT task is measured before and after modulating key human central nervous system (CNS) neurotransmitters and receptor systems (e.g., cholinergic, serotonergic, noradrenergic, and dopaminergic systems). The results of these studies indicate a primarily cholinergic basis for IT, although other aspects of psychometric intelligence may have serotonergic and dopaminergic determinants in addition to a cholinergic basis. The results are consistent with data reporting cholinergic depletion and impaired IT performance in dementia of the Alzheimer's type (DAT). Speculatively, we propose that compounds that enhance the release of the neurotransmitter acetylcholine (Ach) will improve IT and the variance that IT shares with IQ test performance.     

Cortical Acetylcholine, Reality Distortion, Schizophrenia, and Lewy Body Dementia: Too Much or Too Little Cortical Acetylcholine?

Aberrations in cortical cholinergic transmission have been hypothesized to mediate the development and manifestation of psychotic cognition. Based primarily on hypotheses about mesolimbic dopaminergic hyperactivity in schizophrenia, the actions of antipsychotic drugs, the trans-synaptic regulation of the excitability of basal forebrain corticopetal cholinergic neurons, and the role of cortical cholinergic inputs in attentional functions, we hypothesized that persistent disinhibition of cortical cholinergic inputs mediates the fundamental cognitive dysfunctions which form the basis for the development of positive symptoms in schizophrenia. In contrast to this hypothesis, Perry and Perry (1995), based on evidence from hallucinating patients with Lewy Body Dementia (LBD), concluded that the extensivelossof cortical acetylcholine allows irrelevant information to enter “conscious awareness” and thus hallucinations to emerge. The discussion of these contrasting hypotheses highlights the need for more dynamic and precise theories describing the cognitive variables and neuronal processes which contribute to the development and manifestation of psychotic cognition. While the hypothesis that a disinhibited cholinergic system mediates the evolution of psychotic symptoms corresponds more convincingly with current theories about the cognitive functions of cortical cholinergic inputs, both hypotheses stress the critical role of cortical acetylcholine in the highest levels of cognitive functioning.     

Stimulus control of maternal responsiveness to Norway rat (Rattus norvegicus) pup ultrasonic vocalizations

Mother rats (Rattus norvegicus; 6 to 8 days postpartum) approach and maintain proximal orientation to a pup that is emitting ultrasonic vocalizations (USVs) far more than do virgin females (W. J. Farrell & J. R. Alberts, 2002). We used a playback regimen to examine the roles of acoustic and nonacoustic cues in regulating maternal proximal orientation toward vocalizing pups. When presented with recorded USVs, mothers of 6- to 8-day-old pups and nulliparous virgin females exhibited equivalent levels of proximal orientation toward the playback speaker. Mothers did show enhanced proximal orientation toward recorded USVs, however, if a silent pup was positioned below the speaker. Pup odors appear to be crucial for the maternal response to vocalizing pups, as peripherally induced anosmia attenuated maternal proximal orientation toward a vocalizing pup. Furthermore, spatial contiguity between olfactory and auditory stimuli was required for a maximal maternal response.     

Vasopressin,glucose homeostasis,and sucrose taste preferences

Previous research indicates that vasopressin-containing (LE) rats are capable of adapting to the stress of food restriction, whereas vasopressin-deficient (DI) rats cannot adapt to this stressor. It has been postulated that abnormalities in glucose metabolism may be one of the factors leading to the demise of food-restricted DI rats. The present study was conducted to determine if taste preferences are altered in DI animals and if the presentation of exogenous glucose, in the form of sucrose solutions, can ameliorate the effects of the stress of food restriction. Four different concentrations of sucrose solutions were presented to LE and DI rats under the food-restricted condition. In both strains, an 8% sucrose solution was preferred over 0%, 16%, and 32% concentrations, with DI rats consuming more of this concentration than LE rats. Thus, when DI rats had the opportunity of maintaining glucose homeostasis by exogenous supplements, they maintained body weight, displayed no stomach pathology, and survived.     

Vasopressin, glucose homeostasis, and sucrose taste preferences

Previous research indicates that vasopressin-containing (LE) rats are capable of adapting to the stress of food restriction, whereas vasopressin-deficient (DI) rats cannot adapt to this stressor. It has been postulated that abnormalities in glucose metabolism may be one of the factors leading to the demise of food-restricted DI rats. The present study was conducted to determine if taste preferences are altered in DI animals and if the presentation of exogenous glucose, in the form of sucrose solutions, can ameliorate the effects of the stress of food restriction. Four different concentrations of sucrose solutions were presented to LE and DI rats under the food-restricted condition. In both strains, an 8% sucrose solution was preferred over 0%, 16%, and 32% concentrations, with DI rats consuming more of this concentration than LE rats. Thus, when DI rats had the opportunity of maintaining glucose homeostasis by exogenous supplements, they maintained body weight, displayed no stomach pathology, and survived.     

奖赏环路与阿片成瘾:喙内侧被盖核的调节作用

喙内侧被盖核(RMTg)位于腹侧被盖区(VTA)的尾部, 富含抑制性的γ-氨基丁酸(GABA)能神经元.RMTg是中脑边缘多巴胺系统的一个综合调节器.它的GABA能神经元接受外侧缰核(LHb)的输入, 然后投射到VTA多巴胺能神经元, 进而抑制多巴胺的释放.这三个脑区是奖赏环路的重要组成部分, 其中RMTg在阿片类物质激活的奖赏环路中尤为重要.阿片类物质主要通过抑制RMTg GABA能神经元使VTA多巴胺能神经元去抑制, 进而激活奖赏系统.因此, RMTg有望成为治疗药物成瘾(尤其是阿片成瘾)的一个重要靶点.此外, 胆碱类物质作用于RMTg的毒蕈碱受体能够抑制阿片类物质诱导的奖赏效应.未来研究应深入探讨RMTg调控的负性奖赏环路, 这对弱化觅药动机,促进消退和戒断具有重要意义.     

Ultrasonic vocalizations as indices of affective states in rats

Adult rats spontaneously vocalize in ultrasonic frequencies. Although these ultrasonic vocalizations (USVs) have been described as by-products of locomotor activity or social signals, accumulating evidence suggests that they may also index anticipatory affective states. Converging ethological, pharmacological, and brain stimulation research indicates that whereas long low-frequency (> 0.3-s, approximately 22-kHz) USVs occur during anticipation of punishment or avoidance behavior, short, high-frequency (< 0.3-s, approximately 50-kHz) USVs typically occur during anticipation of reward or approach behavior. Thus, long 22-kHz USVs may index a state of negative activation, whereas short, 50-kHz USVs may instead index a state of positive activation. This hypothesis has theoretical implications for understanding the brain circuitry underlying mammalian affective states and clinical applicability for modeling hedonic properties of different psychotropic compounds.     

Selection for reduced aggressiveness towards man and dopaminergic activity in Norway rats

The brain dopaminergic system is involved in the process of long-term selection for reduced aggressive reaction towards man in Norway rats. The dopamine levels in the striatum as well as the nucleus accumbens with the tuberculum olfactorium were significantly lower in domesticated rats than in their wild counterparts. A substantial decrease was found in homovanillic acid level in the n. accumbens and tuberculum olfactorium. Specific binding of [³H]spiperone which labels D-2 dopamine receptors was higher in the mesolimbic structure of tame rats, whereas binding of [³H]SCH 23390 (D-1 receptors) was unchanged in this area. No substantial differences were detected in D-1 and D-2 binding in striatum. Apomorphine (0.3 mg/kg) elicited less locomotion in tame animals, reflecting a decrease of sensitivity of postsynaptic dopamine receptors. Tame rats showed fewer aggressive contacts in a foot-shock test than wild rats and the D-2 receptor antagonist sulpiride (25 mg/kg) significantly decreased the foot-shock aggression only in wild rats. Therefore, domestication, which diminishes defensive behavior and emotional reactivity of animals, is associated with decreases of dopamine level in the striatum, changed metabolism of dopamine in mesolimbic system, and an alteration in density and senstivity of D-2 receptors.     

Auditory trace fear conditioning requires perirhinal cortex

The hippocampus is well-known to be critical for trace fear conditioning, but nothing is known about the importance of perirhinal cortex (PR), which has reciprocal connections with hippocampus. PR damage severely impairs delay fear conditioning to ultrasonic vocalizations (USVs) and discontinuous tones (pips), but has no effect on delay conditioning to continuous tones. Here we demonstrate that trace auditory fear conditioning also critically depends on PR function. The trace interval between the CS offset and the US onset was 16s. Pre-training neurotoxic lesions were produced through multiple injections of N-methyl-D-aspartate along the full length of PR, which was directly visualized during the injections. Control animals received injections with phosphate-buffered saline. Three-dimensional reconstructions of the lesion volumes demonstrated that the neurotoxic damage was well-localized to PR and included most of its anterior-posterior extent. Automated video analysis quantified freezing behavior, which served as the conditional response. PR-damaged rats were profoundly impaired in trace conditioning to either of three different CSs (a USV, tone pips, and a continuous tone) as well as conditioning to the training context. Within both the lesion and control groups, the type of cue had no effect on the mean CR. The overall PR lesion effect size was 2.7 for cue conditioning and 3.9 for context conditioning. We suggest that the role of PR in trace fear conditioning may be distinct from some of its more perceptual functions. The results further define the essential circuitry underlying trace fear conditioning to auditory cues.