Functional magnetic resonance imaging in conscious animals: a new tool in behavioural neuroscience research.
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Animals↗
Biomedical subjects
C F Ferris
Publications and source records attributed to C F Ferris.
A dual RF resonator system for high-field functional magnetic resonance imaging of small animals.
A new apparatus has been developed that integrates an animal restrainer arrangement for small animals with an actively tunable/detunable dual radio-frequency (RF) coil system for in vivo anatomical and functional magnetic resonance imaging of small animals at 4.7 T. The radio-frequency coil features an eight-element microstrip line configuration that, in conjunction with a segmented outer copper shield, forms a transversal electromagnetic (TEM) resonator structure. Matching and active tuning/detuning is achieved through fixed/variable capacitors and a PIN diode for each resonator element. These components along with radio-frequency chokes (RFCs) and blocking capacitors are placed on two printed circuit boards (PCBs) whose copper coated ground planes form the front and back of the volume coil and are therefore an integral part of the resonator structure. The magnetic resonance signal response is received with a dome-shaped single-loop surface coil that can be height-adjustable with respect to the animal's head. The conscious animal is immobilized through a mechanical arrangement that consists of a Plexiglas body tube and a head restrainer. This restrainer has a cylindrical holder with a mouthpiece and position screws to receive and restrain the head of the animal. The apparatus is intended to perform anatomical and functional magnetic resonance imaging in conscious animals such as mice, rats, hamsters, and marmosets. Cranial images acquired from fully conscious rats in a 4.7 T Bruker 40 cm bore animal scanner underscore the feasibility of this approach and bode well to extend this system to the imaging of other animals.
Animals↗
Changes in MRI signal intensity during hypercapnic challenge under conscious and anesthetized conditions.
Most functional magnetic resonance imaging (fMRI) studies in animals are conducted under anesthesia to minimize motion artifacts. However, methods and techniques have been developed recently for imaging fully conscious rats. Functional MRI studies on conscious animals report enhanced BOLD signal changes as compared to the anesthetized condition. In this study, rats were exposed to different concentrations of carbon dioxide (CO(2)) while conscious and anesthetized to test whether cerebrovascular reactivity may be contributing to these enhanced BOLD signal changes. Hypercapnia produced significantly greater increases in MRI signal intensity in fully conscious animals (6.7-13.3% changes) as when anesthetized with 1% isoflurane (3.2-4.9% changes). In addition, the response to hypercapnia was more immediate in the conscious condition (< 30s) with signal risetimes twice as fast as in the anesthetized state (60s). Both cortical and subcortical brain regions showed a robust, dose- dependent increase in MRI signal intensity with hypercapnic challenge while the animals were conscious but little or no change when anesthetized. Baseline variations in MRI signal were higher while animals were conscious but this was off set by greater signal intensity changes leading to a greater contrast-to-noise ratio, 13.1 in conscious animals, as compared to 8.0 in the anesthetized condition. In summary, cerebral vasculature appears to be more sensitive to hypercapnic challenge in the conscious condition resulting in enhanced T2* MRI signal intensity and the potential for better BOLD signal changes during functional imaging.
Anesthesia↗
Vasopressin-dependent flank marking in golden hamsters is suppressed by drugs used in the treatment of obsessive-compulsive disorder.
BACKGROUND: Alterations in arginine vasopressin regulation and secretion have been proposed as one possible biochemical abnormality in patients with obsessive-compulsive disorder. In golden hamsters, arginine vasopressin microinjections into the anterior hypothalamus trigger robust grooming and flank marking, a stereotyped scent marking behaviors. The intensity and repetition of the behaviors induced by arginine vasopressin is somewhat reminiscent of Obsessive Compulsive Disorder in humans. The present experiments were carried out to test whether pharmacological agents used to alleviate obsessive compulsive disorder could inhibit arginine vasopressin-induced flank marking and grooming. RESULTS: Male golden hamsters were treated daily for two weeks with either vehicle, fluoxetine, clomipramine, or desipramine (an ineffective drug), before being tested for arginine vasopressin-induced flank marking and grooming. Flank marking was significantly inhibited in animals treated with fluoxetine or clomipramine but unaffected by treatment with desipramine. Grooming behavior was not affected by any treatment. CONCLUSION: These data suggest that arginine vasopressin-induced flank marking may serve as an animal model for screening drugs used in the control of Obsessive Compulsive Disorder.
Adrenergic Uptake Inhibitors↗
Functional imaging of brain activity in conscious monkeys responding to sexually arousing cues.
Olfactory cues can elicit intense emotional responses. This study used fMRI in male common marmoset monkeys to identify brain areas associated with sexual arousal in response to odors of ovulating female monkeys. Under light anesthesia, monkeys were secured in a specially designed restrainer and positioned in a 9.4 T magnetic resonance spectrometer. When fully conscious, they were presented with the scents of both ovariectomized and ovulating monkeys. The sexually arousing odors of the ovulating monkeys enhanced signal intensity in the preoptic area and anterior hypothalamus compared to the odors of ovariectomized monkeys. These data corroborate previous findings in monkeys based on invasive electrical lesion and stimulation techniques and demonstrate the feasibility of using non-invasive functional imaging on fully conscious common marmosets to study cue-elicited emotional responses.
Animals↗
Early androgen treatment decreases cognitive function and catecholamine innervation in an animal model of ADHD.
The spontaneously hypertensive rat (SHR) has been used as an animal model of attention deficit hyperactivity disorder (ADHD). The present study was designed to determine whether exposure to elevated androgen levels early in development demonstrated impairments in cognitive functioning, neuroendocrine control, and brain development parallel to those seen in ADHD children. The animals (SHR and Wistar (WKY) controls) were implanted with testosterone on postnatal day 10 and tested for behavior in a spatial cognition paradigm on postnatal day 45. Plasma samples were collected for determination of adrenocorticotrophin hormone (ACTH) and corticosterone levels as indicators of the basal tone of the pituitary-adrenal neuroendocrine axis. In addition, the density of tyrosine hydroxylase-immunoreactive fibers (an indicator of catecholamine innervation) in the frontal cortex was compared between animals. The current data show that early testosterone treatment in SHR animals resulted in additional deficits in spatial memory in the water maze, but was ineffective in altering the response of WKY animals. Furthermore, SHR rats had high basal ACTH and low corticosterone levels that may indicate a dysfunctional stress axis similar to other reports in humans with persistent ADHD. Finally, there was a further suppression of tyrosine hydroxylase-immunoreactivity in the frontal cortex of androgen-treated SHR rats. These results support the hypothesis that early androgen treatment may support the neurobiology of animals with genetic predisposition to hyperactivity, impulsivity and inattention in a manner consistent with the enhanced expression of ADHD-like behaviors.
Adrenocorticotropic Hormone↗
Adolescent stress and neural plasticity in hamsters: a vasopressin-serotonin model of inappropriate aggressive behaviour.
Animal studies show that arginine vasopressin facilitates aggression, while serotonin (5-HT) inhibits aggression by blocking the activity of the vasopressin system. Clinical studies report that subjects with a history of 'fighting and assault' show a significant positive correlation between cerebrospinal fluid concentrations of vasopressin and aggression in the presence of a hyporeactive 5-HT system. Thus, in animals and humans, a hyporeactive 5-HT system may result in enhanced vasopressin activity and increased aggression. Can the stress of emotional and physical insult, i.e. threat and attack, during adolescence affect the development of the vasopressin and 5-HT systems and alter normal aggressive behaviour in early adulthood? Adolescent male golden hamsters were weaned at postnatal day 25, and stressed for 2 weeks by daily 1 h bouts of threat and attack by adult hamsters. Male littermates were run in a parallel stress study using daily 1 h trials of isolation in a novel environment. During early adulthood, on postnatal day 45, 3 days after the cessation of stress trials, animals were tested for aggression in a resident: intruder model. The results show a context-dependent change in aggression. Animals with a history of abuse show exaggerated attack behaviour toward smaller males compared to littermates with a history of isolation stress. Conversely, when confronted by males of equal size, animals with a history of abuse show diminished aggression and increased submission compared to controls. It was determined that the density of vasopressin fibres and neurones in the hypothalamus is lower in abused animals compared to controls. In contrast, the number of 5-HT terminals within the hypothalamus is higher in abused animals compared to controls. These results provide evidence in an animal model that stress in the form of threat and attack during adolescence can alter the balance between vasopressin and 5-HT in the brain, resulting in inappropriate aggressive behaviour in early adulthood.
Aggression↗
Neural connections of the anterior hypothalamus and agonistic behavior in golden hamsters.
In male golden hamsters, offensive aggression is regulated by an interaction between arginine-vasopressin and serotonin at the level of the anterior hypothalamus. The present studies were conducted to study a neural network underlying this interaction. The connections of the anterior hypothalamus were examined by retrograde and anterograde tracing in adult male hamsters. Several limbic areas were found to contain both types of tracing suggesting reciprocal connections with the anterior hypothalamus. Their functional significance relating to the consummation of aggression was tested by comparing neuronal activity (examined through quantification of c-Fos-immunolabeling) in two groups of animals. Experimental animals were sacrificed after attacking an intruder. Control animals were sacrificed after exposure to a woodblock carrying the odor of an intruder that elicited behaviors related to offensive aggression without its consummation. An increased density of Fos-immunoreactivity was found in experimental animals within the medial amygdaloid nucleus, ventrolateral hypothalamus, bed nucleus of the stria terminalis and dorsolateral part of the midbrain central gray. These data suggest that these areas are integrated in a neural network centered on the anterior hypothalamus and involved in the consummation of offensive aggression. Finally, c-Fos-immunoreactivity was combined with labeling of serotonin and vasopressin neurons to identify sub-populations particularly associated with offensive aggression. Vasopressin neurons in the nucleus circularis and medial division of the supraoptic nucleus showed increased neuronal activity in the fighters, supporting their role in the control of offensive aggression.
Aggression↗
Galanin antagonizes vasopressin-stimulated flank marking in male golden hamsters.
Microinjection of vasopressin (VP) into the anterior hypothalamus (AH) of golden hamsters induces a rapid bout of flank marking, a stereotyped scent marking behavior used for olfactory communication. In rats, VP is colocalized with galanin (GAL) in several brain regions. GAL has been shown to antagonize the postsynaptic actions of other cosecreted neurotransmitters including acetylcholine and norepinephrine; however, the ability of GAL to modulate the postsynaptic actions of VP has not been assessed. Here, we report that coadministration of GAL can block VP-induced flank marking in golden hamsters in a dose dependent manner. These findings provide the first evidence in any species that GAL can antagonize the central actions of VP. Using slice binding and receptor autoradiography, we have identified GAL binding sites in the AH and two other regions implicated in flank marking behavior (the lateral septum and central grey). These findings raise the possibility that endogenous GAL may function as an inhibitory modulator of this stereotypic scent marking behavior.
Animals↗
Absence of vasopressin expression by galanin neurons in the golden hamster: implications for species differences in extrahypothalamic vasopressin pathways.
In golden hamsters, there is a complete absence of the small diameter vasopressin (VP) neurons in the bed nucleus of the stria terminalis (BST) and medial amygdala (Me) which have been shown to exhibit steroid dependency and sexual dimorphism in many other rodent species. In rats, VP in the BST/Me is always colocalized with the neuropeptide galanin (GAL) and the sex difference in VP cell number appears to result from a sex difference in the number of GAL neurons which coexpress VP. Likewise, we reasoned that the species difference in extrahypothalamic VP pathways present in the golden hamster could result from a reduced coexpression of VP by GAL neurons in these regions. Here, we used in situ hybridization histochemistry to determine whether GAL mRNA expressing neurons are present in the BST and Me of golden hamsters despite the absence of VP expression in these regions. In addition, we have used slice binding and receptor autoradiography to identify specific GAL binding sites in the lateral septum, a probable target region of BST/Me neurons, and in situ hybridization to confirm that some of these binding sites correspond to the GALR1 GAL receptor subtype. Our findings indicate that the absence of VP expression in the BST/Me of golden hamsters results from a failure of extrahypothalamic GAL neurons to express the VP phenotype. Because GAL is expressed in the extended amygdaloid complex and GAL receptors are present in the septum of golden hamsters, GAL may play a role in modulating functions previously attributed to BST/Me pathways.
Amygdala↗
Comparison of evoked cortical activity in conscious and propofol-anesthetized rats using functional MRI.
Changes in cortical activity during foot shock were assessed under conscious and propofol-anesthetized conditions using functional magnetic resonance imaging (fMRI). Increases in signal intensity were observed in the contralateral somatosensory cortex in response to electrical shock of the hindpaw under both conditions. These increases in cortical signal ranged from 6% to 26% while awake and from 1% to 6% under propofol anesthesia. In each of the six animals studied, the largest increase in blood oxygenation level-dependent (BOLD)-based signal intensity was observed during consciousness. In three of six animals, propofol anesthesia depressed signal intensity by as much as 10-fold, showing that the level of cortical activity during foot shock is dampened by anesthesia. These results indicate it would be advantageous to use fully conscious animals to maximize BOLD-based MRI signal in certain behavioral studies using MR spectrometers with modest field strengths (1.0-2.0 T).
Anesthesia, General↗
Serotonin regulation of aggressive behavior in male golden hamsters (Mesocricetus auratus).
These studies examined the neurochemistry and neuroanatomy of the serotonin (5-HT) system innervating the anterior hypothalamus (AH) and the interaction of 5-HT receptor agonists with arginine vasopressin (AVP) in the regulation of offensive aggression in golden hamsters. Because specific 5-HT1A, 5-HT1B, and AVP V1A binding sites were observed within the AH by in vitro autoradiography, the hamsters were tested for offensive aggression after microinjections of AVP in combination with either the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetraline (DPAT) or the 5-HT1B agonist CGS-12066A (CGS) directly within the AH. Though treatment with DPAT resulted in a dose-dependent inhibition of AVP-facilitated offensive aggression, CGS was ineffective. In addition, a retrograde tracer was injected within the AH to localize the distribution of 5-HT neurons projecting to the area. Retrogradely labeled 5-HT neurons were found within the dorsal, median, and caudal linear raphe nuclei and are suspected to inhibit AVP-facilitated offensive aggression by an activation of 5-HT1A receptors in the AH.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Imaging brain activity in conscious animals using functional MRI.
Functional magnetic resonance imaging (fMRI) in humans has helped improve our understanding of the neuroanatomical organization of behavior. Unfortunately, fMRI in animal studies has not kept pace with the human work. Experiments are limited because animals must be anesthetized to prevent motion artifacts, precluding most studies involving neuroimaging of brain activity during behavior. The present study tested a newly developed head and body holder for performing fMRI in fully conscious animals. Significant changes in signal intensities were observed in the somatosensory cortex of conscious rats in response to electrical shock of the hindpaw. These changes in evoked signal ranged between 4 and 19% and were accompanied by significant increases in local cerebral blood flow. The fMRI study was performed with a 2.0-Tesla spectrometer. Using this non-invasive method of imaging brain activity in conscious animals, it is now possible to perform developmental studies in animal models of neurological and psychiatric disorders.
Animals↗
Behavioral and neurobiological consequences of social subjugation during puberty in golden hamsters.
In golden hamsters, offensive aggression is facilitated by vasopressin and inhibited by serotonin. We tested whether these neurotransmitter systems respond to modifications resulting from the stress of threat and attack (i.e., social subjugation) during puberty. Male golden hamsters were weaned at postnatal day 25 (P25), exposed daily to aggressive adults from P28 to P42, and tested for offensive aggression as young adults (P45). The results showed a context-dependent alteration in aggressive behavior. Subjugated animals were more likely to attack younger and weaker intruders than nonsubjugated controls. Conversely, subjugated animals were less likely to attack animals of similar size and age. After testing, the animals were killed, and their brains were collected to determine whether these behavioral changes are underlined by changes in the vasopressin and serotonin systems. Social subjugation resulted in a 50% decrease in vasopressin levels within the anterior hypothalamus, a site involved in the regulation of aggression. Furthermore, whereas the density of vasopressin-immunoreactive fibers within the area was not significantly altered in subjugated animals, the number of serotonin-immunoreactive varicosities within the anterior hypothalamus and lateral septum was 20% higher in subjugated animals than in their controls. These results establish puberty as a developmental period sensitive to environmental stressors. Furthermore, the results show that changes in the vasopressin and serotonin systems can correlate with behavioral alterations, supporting the role of these two neurotransmitters in the regulation of aggression.
Aggression↗
Cerebrospinal fluid vasopressin levels: correlates with aggression and serotonin function in personality-disordered subjects.
BACKGROUND: Animal studies suggest that central vasopressin plays a facilitatory role in aggressive behavior. To examine this possibility in humans, the relationship between cerebrospinal fluid (CSF) arginine vasopressin (AVP) and indices of aggression and central serotonin system function was examined in personality-disordered subjects. METHODS: We used CSF (AVP), CSF 5-hydroxyindoleacetic acid, and the prolactin response to d-fenfluramine challenge (PRL[d-FEN]) as central indices of vasopressin and serotonergic system function, respectively, in 26 subjects who met the DSM-IV criteria for personality disorder. Measures of aggression and impulsivity included the Life History of Aggression assessment and the Barratt Impulsiveness Scales. RESULTS: The CSF AVP level was correlated directly with life history of general aggression and aggression against persons and inversely with PRL[d-FEN] responses (but not with CSF 5-hydroxyindoleacetic acid), which in turn was correlated inversely with these 2 measures of life history of aggression. The positive relationship between CSF AVP and life history of aggression remained even when the variance associated with PRL[d-FEN] responses in these subjects was accounted for. CONCLUSION: Central AVP may play a role in enhancing, while serotonin plays a role in inhibiting, aggressive behavior in personality-disordered individuals. In addition to the possibility of central AVP and serotonin interacting to influence human aggression, central AVP may also influence human aggressive behavior through a mechanism independent of central serotonin in personality-disordered subjects.
Adult↗
Voluntary ethanol consumption in male adolescent hamsters increases testosterone and aggression.
The immediate and long-term biologic and behavioral consequences of voluntary ethanol (EtOH) exposure during male adolescence are unknown. In the present study, male golden hamsters voluntarily drank from a 15% EtOH solution in addition to consuming dry laboratory chow and water ad lib from Postnatal Day 25 to Postnatal Day 43. Over this adolescent period, they drank an average of 13 g/kg/day of EtOH, resulting in a mean blood EtOH concentration of ca. 53 mg %. On Postnatal Day 35, a period of enhanced sensitization and activation of the gonadal axis, testosterone levels were twice as high in EtOH animals than in sucrose-yoked controls. However, this difference disappeared by Postnatal Day 53, as EtOH and control animals showed comparable adult levels of plasma testosterone. When tested for aggression several days after the cessation of EtOH exposure, hamsters showed enhanced attack behavior toward smaller intruders placed into their home cage. These results suggest that voluntary EtOH exposure during male adolescence has specific neuroendocrine effects with lasting behavioral consequences.
Aggression↗
Flank-marking behavior and the neural distribution of vasopressin innervation in golden hamsters with suprachiasmatic lesions.
In golden hamsters, microinjections of arginine-vasopressin (AVP) within the anterior hypothalamus trigger a stereotyped scent-marking behavior, flank marking. Our experiment was carried out to test the contribution of AVP neurons within the suprachiasmatic nucleus (SCN) in the control of this behavior. Our results suggest that the SCN does not contribute to flank-marking behavior. Whereas SCN lesions disrupted circadian rhythms of wheel running, the same lesions did not disrupt flank-marking. The results also suggest that neurons located outside the SCN contribute significantly to the vasopressinergic innervation of the brain and the expression of AVP-dependent behaviors, such as flank-marking behavior. Although AVP-immunoreactive fibers were severely (ca. 95%) depleted from several forebrain areas in SCN-lesioned hamsters, the effect of the lesions was much more limited within the forebrain areas involved in flank-marking behavior as well as within the midbrain and hindbrain.
Animals↗
Vasopressin/serotonin interactions in the anterior hypothalamus control aggressive behavior in golden hamsters.
Studies in several species of rodents show that arginine vasopressin (AVP) acting through a V1A receptor facilitates offensive aggression, i.e., the initiation of attacks and bites, whereas serotonin (5-HT) acting through a 5-HT1B receptor inhibits aggressive responding. One area of the CNS that seems critical for the organization of aggressive behavior is the basolateral hypothalamus, particularly the anterior hypothalamic region. The present studies examine the neuroanatomical and neurochemical interaction between AVP and 5-HT at the level of the anterior hypothalamus (AH) in the control of offensive aggression in Syrian golden hamsters. First, specific V1A and 5-HT1B binding sites in the AH are shown by in vitro receptor autoradiography. The binding for each neurotransmitter colocalizes with a dense field of immunoreactive AVP and 5-HT fibers and putative terminals. Putative 5-HT synapses on AVP neurons in the area of the AH are identified by double-staining immunocytochemistry and laser scanning confocal microscopy. These morphological data predispose a functional interaction between AVP and 5-HT at the level of the AH. When tested for offensive aggression in a resident/intruder paradigm, resident hamsters treated with fluoxetine, a selective 5-HT reuptake inhibitor, have significantly longer latencies to bite and bite fewer times than vehicle-treated controls. Conversely, AVP microinjections into the AH significantly shorten the latency to bite and increase biting attacks. The action of microinjected AVP to increase offensive aggression is blocked by the pretreatment of hamsters with fluoxetine. These data suggest that 5-HT inhibits fighting, in part, by antagonizing the aggression-promoting action of the AVP system.
Aggression↗