Neural circuitry of emotion regulation: Effects of appraisal, attention, and cortisol administration.

Psychosocial well-being requires effective regulation of emotional responding in context of threat or stress. Neuroimaging studies have focused on instructed, volitional regulation (e.g., reappraisal or distancing), largely ignoring implicit regulation that does not involve purposeful effort to alter emotional experience. These implicit processes may or may not involve the same neural pathways as explicit regulatory strategies. We examined the neurobiology of implicit emotional regulation processes and the impact of the stress hormone cortisol on these processes. Our study task employed composite pictures of faces and places to examine neural activity during implicit emotional processing (of emotional faces), while these responses were implicitly regulated by attention shift away from the emotionally evocative stimuli, and while subjects reflectively appraised their own emotional response to them. Subjects completed the task in an fMRI scanner after random assignment to receive placebo or hydrocortisone (HCT), an orally administered version of cortisol. Implicit emotional processing activated insula/IFG, dACC/dMPFC, midbrain and amygdala. With attention shifting, we saw diminished signal in emotion generating/response regions (e.g., amygdala) and increased activations in task specific attention regions like parahippocampus. With appraisal of emotions, we observed robust activations in medial prefrontal areas, where activation is also seen in instructed reappraisal studies. We observed no main effects of HCT administration on brain, but males and females showed opposing neural effects in prefrontal areas. The data suggest that different types of emotion regulation utilize overlapping circuits, but with some strategy specific activation. Further study of the dimorphic sex response to cortisol is needed.

Influence of acute caffeine on 50-kHz ultrasonic vocalizations in male adult rats and relevance to caffeine-mediated psychopharmacological effects.

To further characterize caffeine-mediated psychopharmacological effects, the present study investigated whether acute caffeine (3, 10, 30, 50 mg/kg i.p.) exerted any influence on the emission and features of ultrasonic vocalizations (USVs), which are thought to index changes involving emotional state, in male adult rats. The results obtained demonstrate that caffeine can trigger modifications in the maximum peak frequency and bandwidth of the 50-kHz range USVs. However, such an effect was not accompanied by a significant elevation in the number of 50-kHz USVs, relative to administration of vehicle. Under the same experimental conditions, acute amphetamine (2 mg/kg i.p.) robustly elevated the number of 50-kHz USVs emitted by rats, although it did not affect the maximum peak frequency and bandwidth of USVs. Thus, both qualitative and quantitative differences in the effects exerted by caffeine and amphetamine on 50-kHz USVs were observed. Taken together, these findings further clarify the features of caffeine-mediated psychopharmacological effects, and may help to elucidate the differences between the central effects of caffeine and those elicited by other psychostimulants.

Reduction of dopamine synaptic activity: degradation of 50-kHz ultrasonic vocalization in rats.

Vocal deficits are prevalent and debilitating in Parkinson's disease. These deficits may be related to the initial pathology of the nigrostriatal dopamine neurons and resulting dopamine depletion, which contributes to dysfunction of fine motor control in multiple functions. Although vocalization in animals and humans may differ in many respects, we evaluated complex (50-kHz) ultrasonic mate calls in 2 rat models of Parkinson's disease, including unilateral infusions of 6-hydroxydopamine to the medial forebrain bundle and peripheral administration of a nonakinesia dose of the dopamine antagonist haloperidol. We examined the effects of these treatments on multiple aspects of the acoustic signal. The number of trill-like (frequency modulated) 50-kHz calls was significantly reduced, and appeared to be replaced by simpler (flat) calls. The bandwidth and maximum intensity of simple and frequency-modulated calls were significantly decreased, but call duration was not. Our findings suggest that the nigrostriatal dopamine pathway is involved to some extent in fine sensorimotor function that includes USV production and complexity.

Limb use and complex ultrasonic vocalization in a rat model of Parkinson's disease: deficit-targeted training.

Recent evidence in animal models of Parkinson's disease (PD) suggests that exercise and other forms of motor enhancement can be beneficial when applied during the degeneration of dopamine neurons. Behaviours that depend on adequate levels of striatal dopamine may provide particularly favourable targets for therapeutic motor interventions. Task-specific motor enrichment procedures have been used to improve functional and neural outcomes following unilateral infusions of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway in rats. In contrast, forced non-use procedures can exaggerate the degree of degeneration. Limb-use akinesia and ultrasonic vocalization in the 50-kHz range may be useful behavioural indices of nigrostriatal integrity and may model common deficits found in PD. These deficits in movement initiation and fine sensorimotor control are potential targets for early training interventions.

Syllable acoustics, temporal patterns, and call composition vary with behavioral context in Mexican free-tailed bats.

Recent research has shown that some bat species have rich vocal repertoires with diverse syllable acoustics. Few studies, however, have compared vocalizations across different behavioral contexts or examined the temporal emission patterns of vocalizations. In this paper, a comprehensive examination of the vocal repertoire of Mexican free-tailed bats, T. brasiliensis, is presented. Syllable acoustics and temporal emission patterns for 16 types of vocalizations including courtship song revealed three main findings. First, although in some cases syllables are unique to specific calls, other syllables are shared among different calls. Second, entire calls associated with one behavior can be embedded into more complex vocalizations used in entirely different behavioral contexts. Third, when different calls are composed of similar syllables, distinctive temporal emission patterns may facilitate call recognition. These results indicate that syllable acoustics alone do not likely provide enough information for call recognition; rather, the acoustic context and temporal emission patterns of vocalizations may affect meaning.

Qualitative changes in ultrasonic vocalization in rats after unilateral dopamine depletion or haloperidol: a preliminary study.

The sensorimotor speech/voice deficits associated with Parkinson disease have been well documented in humans. They are largely resistant to pharmacological and surgical treatment, but respond to intensive speech therapy. The mechanisms underlying this phenomenon are not well understood and are difficult to systematically test in humans. Thus, we turn to the rat as a model. The purpose of this study is to compare the ultrasonic vocalization (USV) of rats in three conditions: control, haloperidol-induced transient dopamine depletion, and unilateral 6-hydroxydopamine (6-OHDA) induced moderately-severe degeneration of dopamine neurons. It was hypothesized that both dopamine-altered conditions would lead to a change in the features of the USV acoustic signal. Results demonstrated that bandwidth decreased in the dopamine-altered rats. This is the first study to document a degradation of the acoustic signal of frequency-modulated 50-kHz calls as a result of interfering with dopamine synaptic transmission in rats. The data suggest that mild transient dopamine depletion with haloperidol or even unilateral degeneration of dopamine neurons is associated with changes in the USV acoustic signal. Dopaminergic dysfunction influences USV quality without reducing the number of calls. This study provides a foundation to examine the role of dopamine in sensorimotor processes underlying USV production and potentially to explore treatments for dopamine deficiency-related impaired vocal outcome.

Childhood poverty and recruitment of adult emotion regulatory neurocircuitry.

One in five American children grows up in poverty. Childhood poverty has far-reaching adverse impacts on cognitive, social and emotional development. Altered development of neurocircuits, subserving emotion regulation, is one possible pathway for childhood poverty's ill effects. Children exposed to poverty were followed into young adulthood and then studied using functional brain imaging with an implicit emotion regulation task focused. Implicit emotion regulation involved attention shifting and appraisal components. Early poverty reduced left dorsolateral prefrontal cortex recruitment in the context of emotional regulation. Furthermore, this emotion regulation associated brain activation mediated the effects of poverty on adult task performance. Moreover, childhood poverty also predicted enhanced insula and reduced hippocampal activation, following exposure to acute stress. These results demonstrate that childhood poverty can alter adult emotion regulation neurocircuitry, revealing specific brain mechanisms that may underlie long-term effects of social inequalities on health. The role of poverty-related emotion regulatory neurocircuitry appears to be particularly salient during stressful conditions.

Sex differences in the influence of social context, salient social stimulation and amphetamine on ultrasonic vocalizations in prairie voles.

Prairie voles (Microtus ochrogaster) are a socially monogamous rodent species and their cooperative behaviors require extensive communication between conspecifics. Rodents use ultrasonic vocalizations (USVs) to communicate and because a prairie vole breeder pair must engage in extensive cooperation for successful reproduction, auditory communication may be critical for this species. Therefore, we sought to characterize USVs in adult male and female prairie voles, and to determine how these calls are influenced by social context, salient social stimuli and the psychostimulant drug of abuse amphetamine (AMPH). Here, we characterize prairie vole USVs by showing the range of frequencies of prairie vole USVs, the proportion of various call types, how these call types compare between males and females, and how they are influenced by social stimulation and AMPH. AMPH caused a robust increase in the number of USVs in both males and females and there was a dramatic sex difference in the complexity of call structures of AMPH-induced USVs, with males emitting more elaborate calls. Moreover, we show that novel (i.e. salient) social cues evoked differential increases in USVs across sex, with males showing a much more robust increase in USV production, both with respect to the frequency and complexity of USV production. Exposure to an estrous female in particular caused an extraordinary increase in USVs in male subjects. These data suggest that USVs may be a useful measure of social motivation in this species, including how social behaviors can be impacted by drugs of abuse.

Interaction of the ADRB2 gene polymorphism with childhood trauma in predicting adult symptoms of posttraumatic stress disorder.

IMPORTANCE: Posttraumatic stress disorder (PTSD), while highly prevalent (7.6% over a lifetime), develops only in a subset of trauma-exposed individuals. Genetic risk factors in interaction with trauma exposure have been implicated in PTSD vulnerability. OBJECTIVE: To examine the association of 3755 candidate gene single-nucleotide polymorphisms with PTSD development in interaction with a history of childhood trauma. DESIGN, SETTING, AND PARTICIPANTS: Genetic association study in an Ohio National Guard longitudinal cohort (n = 810) of predominantly male soldiers of European ancestry, with replication in an independent Grady Trauma Project (Atlanta, Georgia) cohort (n = 2083) of predominantly female African American civilians. MAIN OUTCOMES AND MEASURES: Continuous measures of PTSD severity, with a modified (interview) PTSD checklist in the discovery cohort and the PTSD Symptom Scale in the replication cohort. RESULTS: Controlling for the level of lifetime adult trauma exposure, we identified the novel association of a single-nucleotide polymorphism within the promoter region of the ADRB2 (Online Mendelian Inheritance in Man 109690) gene with PTSD symptoms in interaction with childhood trauma (rs2400707, P = 1.02 × 10-5, significant after correction for multiple comparisons). The rs2400707 A allele was associated with relative resilience to childhood adversity. An rs2400707 × childhood trauma interaction predicting adult PTSD symptoms was replicated in the independent predominantly female African American cohort. CONCLUSIONS AND RELEVANCE: Altered adrenergic and noradrenergic function has been long believed to have a key etiologic role in PTSD development; however, direct evidence of this link has been missing. The rs2400707 polymorphism has been linked to function of the adrenergic system, but, to our knowledge, this is the first study to date linking the ADRB2 gene to PTSD or any psychiatric disorders. These findings have important implications for PTSD etiology, chronic pain, and stress-related comorbidity, as well as for both primary prevention and treatment strategies.

A cocaine cue is more preferred and evokes more frequency-modulated 50-kHz ultrasonic vocalizations in rats prone to attribute incentive salience to a food cue.

RATIONALE: Individuals vary considerably in the extent to which they attribute incentive salience to food-associated cues. OBJECTIVES: We asked whether individuals prone to attribute incentive salience to a food cue are also prone to attribute incentive properties to a stimulus associated with a drug of abuse-cocaine. METHODS: We first identified those rats that attributed incentive salience to a food cue by quantifying the extent to which they came to approach and engage a food cue. We then used a conditioned place preference procedure to pair an injection of 10 mg/kg cocaine (i.p.) with one distinct floor texture (grid or holes) and saline with another. Following 8 days of conditioning, each rat was given a saline injection and placed into a chamber that had both floors present. We measured the time spent on each floor, and also 50-kHz ultrasonic vocalizations, which have been associated with positive affective states. RESULTS: Rats that vigorously engaged the food cue ("sign trackers") expressed a preference for the cocaine-paired floor compared to those that did not ("goal trackers"). In addition, sign trackers made substantially more frequency-modulated 50-kHz vocalizations when injected with cocaine and when later exposed to the cocaine cue. CONCLUSIONS: Rats prone to attribute incentive salience to a food cue are also prone to attribute incentive motivational properties to a tactile cue associated with cocaine. We suggest that individuals prone to attribute incentive salience to reward cues will have difficulty resisting them and, therefore, may be especially vulnerable to develop impulse control disorders, including addiction.

Assessing the role of dopamine in limb and cranial-oromotor control in a rat model of Parkinson's disease.

UNLABELLED: Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by sensorimotor dysfunction. The neuropathology of PD includes a loss of dopamine (DA) neurons of the nigrostriatal pathway. Classic signs of the disease include rigidity, bradykinesia, and postural instability. However, as many as 90% of patients also experience significant deficits in speech, swallowing (including mastication), and respiratory control. Oromotor deficits such as these are underappreciated, frequently emerging during the early, often hemi-Parkinson, stage of the disease. In this paper, we review tests commonly used in our labs to model early and hemi-Parkinson deficits in rodents. We have recently expanded our tests to include sensitive models of oromotor deficits. This paper discusses the most commonly used tests in our lab to model both limb and oromotor deficits, including tests of forelimb-use asymmetry, postural instability, vibrissae-evoked forelimb placing, single limb akinesia, dry pasta handling, sunflower seed shelling, and acoustic analyses of ultrasonic vocalizations and pasta biting strength. In particular, we lay new groundwork for developing methods for measuring abnormalities in the acoustic patterns during eating that indicate decreased biting strength and irregular intervals between bites in the hemi-Parkinson rat. Similar to limb motor deficits, oromotor deficits, at least to some degree, appear to be modulated by nigrostriatal DA. Finally, we briefly review the literature on targeted motor rehabilitation effects in PD models. LEARNING OUTCOMES: Readers will: (a) understand how a unilateral lesion to the nigrostriatal pathway affects limb use, (b) understand how a unilateral lesion to the nigrostriatal pathway affects oromotor function, and (c) gain an understanding of how limb motor deficits and oromotor deficits appear to involve dopamine and are modulated by training.

Assessment of ultrasonic vocalizations during drug self-administration in rats.

Drug self-administration procedures are commonly used to study behavioral and neurochemical changes associated with human drug abuse, addiction and relapse. Various types of behavioral activity are commonly utilized as measures of drug motivation in animals. However, a crucial component of drug abuse relapse in abstinent cocaine users is "drug craving", which is difficult to model in animals, as it often occurs in the absence of overt behaviors. Yet, it is possible that a class of ultrasonic vocalizations (USVs) in rats may be a useful marker for affective responses to drug administration, drug anticipation and even drug craving. Rats vocalize in ultrasonic frequencies that serve as a communicatory function and express subjective emotional states. Several studies have shown that different call frequency ranges are associated with negative and positive emotional states. For instance, high frequency calls ("50-kHz") are associated with positive affect, whereas low frequency calls ("22-kHz") represent a negative emotional state. This article describes a procedure to assess rat USVs associated with daily cocaine self-administration. For this procedure, we utilized standard single-lever operant chambers housed within sound-attenuating boxes for cocaine self-administration sessions and utilized ultrasonic microphones, multi-channel recording hardware and specialized software programs to detect and analyze USVs. USVs measurements reflect emotionality of rats before, during and after drug availability and can be correlated with commonly assessed drug self-administration behavioral data such lever responses, inter-response intervals and locomotor activity. Since USVs can be assessed during intervals prior to drug availability (e.g., anticipatory USVs) and during drug extinction trials, changes in affect associated with drug anticipation and drug abstinence can also be determined. In addition, determining USV changes over the course of short- and long-term drug exposure can provide a more detailed interpretation of drug exposure effects on affective functioning.

Repeated intravenous cocaine experience: development and escalation of pre-drug anticipatory 50-kHz ultrasonic vocalizations in rats.

Ultrasonic vocalization (USV) in the 50-kHz range occurs in rats immediately upon first-time exposure to cocaine or amphetamine, and rapidly increases with repetitive drug exposure at the same dose. This sensitized positive-affect response to these drugs of abuse is persistent in that the peak level of USVs again appears when the drug is reintroduced after several weeks of drug discontinuation. The present study explored whether with enough experience USVs might be elicited, and gradually escalate, in anticipation of impending drug delivery. Rats were trained to self-administer (SA) cocaine intravenously by lever pressing 5 days per week for 4 weeks. Yoked rats received experimenter-delivered cocaine matching that of SA rats. USVs and locomotor activity were recorded during each 10-min period prior to 60-min drug access sessions. Extinction trials in which drug access was denied were then carried out over an additional 4-week period. After about a week of cocaine experience, both the SA and yoked groups began to progressively increase USVs when placed in an environment that predicted forthcoming drug exposure. Extinction of anticipatory calls and locomotion occurred over days after drug access ended. USVs may be a useful model for specifically investigating the neural basis of drug anticipation and aid in developing and assessing new addiction treatment strategies for reducing craving and relapse.

Cocaine deprivation effect: cue abstinence over weekends boosts anticipatory 50-kHz ultrasonic vocalizations in rats.

In drug dependence studies, rats are often tested daily with short breaks (such as weekends) spent untested in their home cages. Research on alcohol models has suggested that breaks from continuous testing can transiently enhance self-administration (termed the "alcohol deprivation effect"). The present study explored whether the salience of cocaine-access cues is increased after skipping weekend cocaine and cue exposures. Ultrasonic vocalizations (USVs) of the 50-kHz class are emitted by rats exposed to intravenous cocaine and have been shown to increase with repeated drug exposure at the same dose level (sensitization). The present study found that over the course of several weeks of cocaine self- or yoked-administration pre-drug cues signaling forthcoming access or delivery of cocaine elicited marked amounts of anticipatory 50-kHz USVs, and that weekend deprivation from cues and cocaine exaggerated further the level of calling (more calls on Mondays compared to Fridays). Anticipatory USVs extinguished less rapidly when weekend access to unreinforced cues was denied. The results may have clinical implications, in that intermittently avoiding cues or context may enhance drug cue salience and resistance to extinction.

Repeated intravenous amphetamine exposure: rapid and persistent sensitization of 50-kHz ultrasonic trill calls in rats.

Short 50-kilohertz (kHz) range frequency-modulated ultrasonic vocalizations (USVs) produced by rats and mice are unconditionally elicited by drugs of abuse or electrical stimulation that increase dopamine activity in the nucleus accumbens, and it has been suggested that they reflect "positive affect" or incentive motivational states associated with appetitive behavior. The repeated administration of amphetamine is known to not only produce "psychomotor" sensitization, but also to facilitate a number of appetitive behaviors, including conditioned drug pursuit behavior. We were interested, therefore, in whether amphetamine-induced 50-kHz USVs would also increase with repeated drug exposure. USV recordings were made during 5-min sessions immediately after a saline infusion, and again 4-5h later after 1.0mg/kg intravenous amphetamine exposure. These sessions took place every other day over a 5-day period. A challenge dose of 1.0mg/kg amphetamine was administered 2 weeks later to determine whether sensitization would persist. The initial amphetamine infusion increased 50-kHz USVs relative to the saline infusion. This effect was enhanced over trials and during the amphetamine challenge 2 weeks later. Classification of 50-kHz range call types revealed that complex frequency-modulated trill calls were sensitized by amphetamine, but not flat 50-kHz calls. It is possible that 50-kHz USV recordings could provide a potentially valuable behavioral measure of sensitization linked to enhanced incentive salience and increased tendency to self-administer drugs of abuse.