From emotional arousal to executive action. Role of the prefrontal cortex.

Emotional arousal is caused by the activity of two parallel ascending systems targeting mostly the subcortical limbic regions and the prefrontal cortex. The aversive, negative arousal system is initiated by the activity of the mesolimbic cholinergic system and the hedonic, appetitive, arousal is initiated by the activity of the mesolimbic dopaminergic system. Both ascending projections have a diffused nature and arise from the rostral, tegmental part of the brain reticular activating system.

Water Drinking Behavior Associated with Aversive Arousal in Rats: An Integrative Approach.

Cholinergic muscarinic stimulation of vast areas of the limbic brain induced a well-documented polydipsia in laboratory rats. This excessive water-drinking behavior has not received any convincing biological and physiological interpretation for the last 50 years. This review offers such an interpretation and suggests that cholinergically induced drinking response, mostly by carbachol, is associated with activation of the ascending mesolimbic cholinergic system that serves for initiation of emotional aversive arousal of the organism.

Recent Studies of Rat Ultrasonic Vocalizations-Editorial.

Since the realization that human emotional experiences and behavior evolved from mammalian ancestors and are evolutionary continuations of animal emotional behavior [...

Biological Functions of Rat Ultrasonic Vocalizations, Arousal Mechanisms, and Call Initiation.

This review summarizes all reported and suspected functions of ultrasonic vocalizations in infant and adult rats. The review leads to the conclusion that all types of ultrasonic vocalizations subserving all functions are vocal expressions of emotional arousal initiated by the activity of the reticular core of the brainstem. The emotional arousal is dichotomic in nature and is initiated by two opposite-in-function ascending reticular systems that are separate from the cognitive reticular activating system.

Using rat ultrasonic vocalization to study the neurobiology of emotion: from basic science to the development of novel therapeutics for affective disorders.

The use of ultrasonic vocalizations as an experimental tool for studying emotional states in rodents has led to an increased understanding of the basic science of affect as well as the development of novel diagnostics and therapeutics for the treatment of affective disorders. At the behavioral level, the rules that govern the generation of affective 'feeling' states are similar to those of the psychophysics of sensory perception. Emotions are elicited primarily in response to active social stimuli.

Dissimilar interaction between dopaminergic and cholinergic systems in the initiation of emission of 50-kHz and 22-kHz vocalizations.

Rats emit 22-kHz or 50-kHz ultrasonic vocalizations (USVs) to signal their emotional state to other conspecifics. The 22-kHz USVs signal a negative emotional state while 50-kHz USVs reflect a positive affective state. The initiation of 22-kHz USVs is dependent on the activity of cholinergic neurons within the laterodorsal tegmental nucleus that release acetylcholine along the medial cholinoceptive vocalization strip.

Association of medial corticostriatal regions with amphetamine-induced emission of 50 kHz vocalizations as studied by Zif-268 expression in the rat brain.

Behavioural sensitization of locomotion and 50 kHz ultrasonic vocalizations (USVs) following repeated amphetamine (AMPH) injections in rats has been extensively demonstrated. These two behaviours appear dissociable in their sensitization patterns and are thought to be reflective of underlying emotional states of the organism. Although AMPH is often used to induce 50 kHz USVs there is little research to date on the extent of cortical and subcortical forebrain region involvement in 50 kHz call production associated with the drug.

The antagonistic relationship between aversive and appetitive emotional states in rats as studied by pharmacologically-induced ultrasonic vocalization from the nucleus accumbens and lateral septum.

Rats can emit 22-kHz or 50-kHz ultrasonic vocalizations (USVs) in negative, as well as positive contexts which index their emotional state. 22-kHz USVs are emitted during aversive contexts and can be initiated by activation of the ascending cholinergic pathways originating from the laterodorsal tegmental nucleus or initiated pharmacologically by injection of cholinergic agonists into target areas of these pathways (medial cholinoceptive vocalization strip). Conversely, 50-kHz USVs are emitted during positive pro-social contexts and can be initiated by stimulation of ascending dopaminergic pathways originating from the ventral tegmental area or by injection of dopamine agonists into target areas of these pathways (nucleus accumbens shell).

Intracerebral injection of R-(-)-Apomorphine into the nucleus accumbens decreased carbachol-induced 22-kHz ultrasonic vocalizations in rats.

Rats can produce ultrasonic vocalizations (USVs) in a variety of different contexts that signal their emotional state to conspecifics. Under distress, rats can emit 22-kHz USVs, while during positive pro-social interactions rats can emit frequency-modulated (FM) 50-kHz USVs. It has been previously reported that rats with increasing emission of FM 50-kHz USVs in anticipation of rewarding electrical stimulation or positive pro-social interaction decrease the number of emitted 22-kHz USVs.

Emission of 22 kHz vocalizations in rats as an evolutionary equivalent of human crying: Relationship to depression.

There is no clear relationship between crying and depression based on human neuropsychiatric observations. This situation originates from lack of suitable animal models of human crying. In the present article, an attempt will be made to answer the question whether emission of rat aversive vocalizations (22 kHz calls) may be regarded as an evolutionary equivalent of adult human crying.

Effect of microinjections of dopamine into the nucleus accumbens shell on emission of 50 kHz USV: Comparison with effects of d-amphetamine.

Systemic pharmacological manipulation of dopamine (DA) signaling has been central to many investigations of 50 kHz ultrasonic vocalizations (USVs) in the rat. In particular, the indirect DA releaser d-amphetamine (AMPH) has been used extensively in many such investigations. The possible unique character of the native transmitter relative to DA-stimulating drugs such as AMPH in inducing and modulating emission of 50 kHz USVs has not been investigated.

Non-pharmacological induction of rat 50 kHz ultrasonic vocalization: Social and non-social contexts differentially induce 50 kHz call subtypes.

The emission of 50 kHz ultrasonic vocalizations (USVs) by rats is thought to represent a measurable expression of the individuals underlying emotional state. These calls are also posited as fulfilling important communicative functions among conspecifics. In addition to social situations, 50 kHz USVs are recorded in a variety of reward-related contexts including sugary foods and drink, consumable ethanol, and drugs of abuse.

Rat 50-kHz ultrasonic vocalizations as a tool in studying neurochemical mechanisms that regulate positive emotional states.

Background: Adolescent and adult rats emit 50-kHz ultrasonic vocalizations (USVs) to communicate the appetitive arousal and the presence of positive emotional states to conspecifics.

New Method: Based on its communicative function, emission of 50-kHz USVs is increasingly being evaluated in preclinical studies of affective behavior, motivation and social behavior.

Results: Emission of 50-kHz USVs is initiated by the activation of dopamine receptors in the shell subregion of the nucleus accumbens.

Individual behavioural predictors of amphetamine-induced emission of 50 kHz vocalization in rats.

Measurement of ultrasonic vocalizations (USVs) produced by adult rats represents a highly useful index of emotional arousal. The associations found between 50 kHz USV production and a variety of behavioural and pharmacological protocols increasingly suggests they serve as a marker of positive motivational states. This study used a powerful within-subjects design to investigate the relationships among individual differences in approach to a sweet-food reward, predisposition to emit 50 kHz USVs spontaneously, and 50 kHz USVs emission following acute systemic administration of amphetamine.

Pharmacology of Ultrasonic Vocalizations in adult Rats: Significance, Call Classification and Neural Substrate.

Pharmacological studies of emotional arousal and initiation of emotional states in rats measured by their ultrasonic vocalizations are reviewed. It is postulated that emission of vocalizations is an inseparable feature of emotional states and it evolved from mother-infant interaction. Positive emotional states are associated with emission of 50 kHz vocalizations that could be induced by rewarding situations and dopaminergic activation of the nucleus accumbens and are mediated by D1, D2, and partially D3 dopamine receptors.

The ascending mesolimbic cholinergic system--a specific division of the reticular activating system involved in the initiation of negative emotional states.

The review summarizes evidences from extensive studies suggesting that ascending mesolimbic cholinergic system (AMCS) that terminates in vast areas of forebrain and diencephalic limbic areas is responsible for specific generation of aversive arousal and aversive emotional state. This state is accompanied by emission of threatening and/or alarming vocalizations that served as a quantitative measure of the emotional response. The AMCS originates from the cholinergic neurons within the laterodorsal tegmental nucleus that have widespread and diffuse ascending connections.

Rats selectively bred for low levels of play-induced 50 kHz vocalizations as a model for autism spectrum disorders: a role for NMDA receptors.

Early childhood autism is characterized by deficits in social approach and play behaviors, socio-emotional relatedness, and communication/speech abnormalities, as well as repetitive behaviors. These core neuropsychological features of autism can be modeled in laboratory rats, and the results may be useful for drug discovery and therapeutic development. We review data that show that rats selectively bred for low rates of play-related pro-social ultrasonic vocalizations (USVs) can be used to model social deficit symptoms of autism.

Ethotransmission: communication of emotional states through ultrasonic vocalization in rats.

Adult rats emit two categories of ultrasonic vocalizations, 22 kHz calls and 50 kHz calls. These vocalizations communicate animal's emotional state to other members of the social group. Production of social vocalizations is an evolutionary old activity in vertebrates, and is regulated by well-preserved brain circuitries.

Quinpirole-induced 50 kHz ultrasonic vocalization in the rat: role of D2 and D3 dopamine receptors.

The goal of the present investigation was to study a full dose-response of quinpirole in production of species-specific 50 kHz ultrasonic vocalizations in rats, and to study involvement of D2 and D3 dopamine receptors in this response. Quinpirole, a D2/D3 dopamine agonist with high selectivity for D2 dopamine receptors, was injected into the shell of the nucleus accumbens. Quinpirole induced species-specific 50 kHz ultrasonic vocalizations at a wide range of doses as compared to saline.

Motor and locomotor responses to systemic amphetamine in three lines of selectively bred Long-Evans rats.

The goal of the study was to measure spontaneous and amphetamine-induced motor and locomotor activity in three selectively bred lines of male Long-Evans rats. The number of 50 kHz ultrasonic vocalizations (USVs) emitted in response to heterospecific play with human hand ("tickling") had been measured daily in these lines of rats from 21 to 24 days of age, as a criterion for dividing them into high vocalizing line, low vocalizing line, and random breeding and testing lines. This study sought to determine whether selection of rats based on their affective social-vocalizations also had effects on their locomotor performance and sensitivity to amphetamine.

Activity of cholinergic neurons in the laterodorsal tegmental nucleus during emission of 22kHz vocalization in rats.

It has been postulated that the ascending cholinergic tegmental system is responsible for the initiation of the aversive emotional state with a concomitant alarm vocalization in the rat. It is assumed that the activity of cholinergic neurons of the laterodorsal tegmental nucleus (LDT) will cause release of acetylcholine in the target areas and will initiate the emission of 22kHz vocalizations. The goal of the present study was to test the hypothesis that the cholinergic neurons of the LDT increase their activity during emission of 22kHz alarm calls.

A novel NMDA receptor glycine-site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism.

Deficits in social approach behavior, rough-and-tumble play, and speech abnormalities are core features of autism that can be modeled in laboratory rats. Human twin studies show that autism has a strong genetic component, and a recent review has identified 99 genes that are dysregulated in human autism. Bioinformatic analysis of these 99 genes identified the NMDA receptor complex as a significant interaction hub based on protein-protein interactions.

Positive emotional learning is regulated in the medial prefrontal cortex by GluN2B-containing NMDA receptors.

In rats, hedonic ultrasonic vocalizations (USVs) is a validated model of positive affect and is best elicited by rough-and-tumble play. Here we report that modulation of GluN2B-containing NMDA receptors (NMDAR) in the medial prefrontal cortex (MPFC) is involved in positive emotional learning. Rough and tumble play increased both GluN1 and GluN2B NMDAR subunit mRNA and protein levels in the frontal cortex.

Heightened locomotor-activating effects of amphetamine administered into the nucleus accumbens in adolescent rats.

There is a shift in sensitivity to systemically administered psychostimulants in adolescence, as evidenced by less amphetamine-induced locomotor activity in adolescent compared to adult rodents. Locomotor activating effects of amphetamine are dependent on drug actions in the core of the nucleus accumbens (NAc), but the contribution of this region to age differences in amphetamine sensitivity has not been studied directly. In the present study, we investigated the development of the NAc using targeted injections of amphetamine (0, 3, or 6 μg/side) directly into the NAc core in early (postnatal day 30; P30) or late (P45) adolescence, or in adulthood (P75).

Effects of intraaccumbens amphetamine on production of 50 kHz vocalizations in three lines of selectively bred Long-Evans rats.

Effects of direct injections of amphetamine into the shell of the nucleus accumbens were studied in three lines of Long-Evans rats, two of which had been selected for low and high rates of 50 kHz calls in adolescence in response to a standard social stimulation, and compared to results from randomly selected rats. Injections of amphetamine into the medial shell of the nucleus accumbens significantly increased the number of 50 kHz vocalizations in the high line but not low line, as compared to the random controls. This response was shell specific and antagonized by raclopride.