Analysis of behavioral constraints and the neuroanatomy of fear to the predator odor trimethylthiazoline: a model for animal phobias.

Specific phobias, including animal phobias, are the most common anxiety disorders, and have a strong innate and genetic component. Research on the neurobiology and environmental constraints of innate fear of predators in rodents may be useful in elucidating mechanisms of animal phobias in humans. The present article reviews research on innate fear in rats to trimethylthiazoline (TMT), an odor originally isolated from fox feces. TMT induces unconditioned freezing and other defensive responses that are regulated by the dose of TMT and the shape of the testing environment. Contextual conditioning induced by TMT occurs, but is constrained by the environment. Lesion studies indicate the amygdala circuitry subserving fear conditioning is not necessary for unconditioned fear to TMT. Additionally, a medial hypothalamic defensive circuit also appears not necessary for unconditioned freezing to TMT, whereas circuits that include the medial nucleus of the amygdala and the bed nucleus of the stria terminalis are essential. The importance of these findings of innate predator odor fear in rodents to animal phobias in humans is discussed.

Vasopressin stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia.

Arginine vasopressin (AVP) made by hypothalamic neurons is released into the circulation to stimulate water resorption by the kidneys and restore water balance after blood loss. Patients who lack this antidiuretic hormone suffer from central diabetes insipidus. We observed that many of these patients were anemic and asked whether AVP might play a role in red blood cell (RBC) production. We found that all three AVP receptors are expressed in human and mouse hematopoietic stem and progenitor cells. The AVPR1B appears to play the most important role in regulating erythropoiesis in both human and mouse cells. AVP increases phosphorylation of signal transducer and activator of transcription 5, as erythropoietin (EPO) does. After sublethal irradiation, AVP-deficient Brattleboro rats showed delayed recovery of RBC numbers compared to control rats. In mouse models of anemia (induced by bleeding, irradiation, or increased destruction of circulating RBCs), AVP increased the number of circulating RBCs independently of EPO. In these models, AVP appears to jump-start peripheral blood cell replenishment until EPO can take over. We suggest that specific AVPR1B agonists might be used to induce fast RBC production after bleeding, drug toxicity, or chemotherapy.

The ontogeny of interstimulus interval (ISI) discrimination of the conditioned eyeblink response in rats.

Discrimination of the eyeblink conditioned response (CR) between conditioned stimuli (CSs) of different durations and modalities was examined across development in rats. Interstimulus interval (ISI) discrimination was evident at Postnatal Days 23-34 in Experiment 1, and earlier CR peak latencies and enhanced CR amplitudes were seen to the long CS in the ISI discrimination group relative to a control group receiving the short CS without reinforcement. Experiment 2 showed that early CR peak latencies and enhanced CR amplitudes to the long CS in the ISI discrimination group were due to associative pairing of the short CS and unconditioned stimulus. Experiment 3 demonstrated ISI discrimination in adults that was improved relative to younger subjects, but with no enhancement of CR amplitude to the long CS in the ISI discrimination group. Cerebellar cortical maturation may influence the ontogeny of CR timing.

Using transgenic mouse models to study oxytocin's role in the facilitation of species propagation.

Oxytocin and its receptor are important for a wide range of effects, from social memory to uterine contractions. It is an evolutionarily well-conserved hormone that is particularly important in social and gregarious animals. Research on small mammals has yielded a rich literature on oxytocin's many functions. Recently a new tool has been created that has furthered our understanding of oxytocin's role in behavior: transgenic mice that lack either the ability to synthesize oxytocin or the oxytocin receptor itself. The study of these lines, while still in its infancy, is already bearing fruit and offers the promise of insight into some human disorders characterized by aberrant social behavior.

The medial hypothalamic defensive circuit and 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) induced fear: comparison of electrolytic and neurotoxic lesions.

The neural circuits for unconditioned fear to predator odors (e.g., cat fur odor, trimethylthiazoline, TMT) are not well delineated. A putative neural circuit for predator odor fear, the medial hypothalamic defensive circuit (MHDC), consisting of the anterior hypothalamic (AHN), ventromedial hypothalamic (VMH) and dorsal premammillary nuclei (PMd), has been proposed. Electrolytic and ibotenic acid lesions of the PMd have been shown to reduce unconditioned fear in rats presented with either a cat or cat odor. Whether the PMd, AHN and VMH are involved in unconditioned fear to another predator odor derived from fox feces, 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), has not been explored. The present study compared the effects of electrolytic and neurotoxic lesions of MHDC nuclei in rats on unconditioned fear to TMT and shock-induced contextually conditioned fear, as measured by freezing. Electrolytic lesions of the PMd did not reduce TMT-induced freezing, but diminished post-shock and shock-induced contextually conditioned freezing, suggesting a role for the PMd in contextually conditioned fear. In contrast, electrolytic lesions of the AHN and VMH reduced freezing to TMT while not affecting conditioned fear. However, neither NMDA lesions of the AHN nor ibotenic acid lesions of the VMH reduced freezing in shock-induced conditioned or TMT-induced unconditioned fear paradigms. The data suggest that fibers passing through the AHN and VMH, and not cells in the MHDC, mediate unconditioned freezing to the predator odor TMT.

Oxytocin: the great facilitator of life.

Oxytocin (Oxt) is a nonapeptide hormone best known for its role in lactation and parturition. Since 1906 when its uterine-contracting properties were described until 50 years later when its sequence was elucidated, research has focused on its peripheral roles in reproduction. Only over the past several decades have researchers focused on what functions Oxt might have in the brain, the subject of this review. Immunohistochemical studies revealed that magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei are the neurons of origin for the Oxt released from the posterior pituitary. Smaller cells in various parts of the brain, as well as release from magnocellular dendrites, provide the Oxt responsible for modulating various behaviors at its only identified receptor. Although Oxt is implicated in a variety of "non-social" behaviors, such as learning, anxiety, feeding and pain perception, it is Oxt's roles in various social behaviors that have come to the fore recently. Oxt is important for social memory and attachment, sexual and maternal behavior, and aggression. Recent work implicates Oxt in human bonding and trust as well. Human disorders characterized by aberrant social interactions, such as autism and schizophrenia, may also involve Oxt expression. Many, if not most, of Oxt's functions, from social interactions (affiliation, aggression) and sexual behavior to eventual parturition, lactation and maternal behavior, may be viewed as specifically facilitating species propagation.

Spatial conditional discrimination learning in developing rats.

The present study established an effective procedure for studying spatial conditional discrimination learning in juvenile rats using a T-maze. Wire mesh located on the floor of the maze as well as a second, identical T-maze apparatus served as conditional cues which signaled whether a left or a right response would be rewarded. In Experiment 1, conditional discrimination was evident on Postnatal Day (PND) 30 when mesh+maze or maze-alone were the conditional cues, but not when mesh-alone was the cue. Experiment 2 confirmed that mesh-alone was sufficiently salient to support learning of a simple (nonconditional) discrimination. Its failure to serve as a conditional cue in Experiment 1 does not reflect its general ineffectiveness as a stimulus. Experiment 3 confirmed that the learning shown in Experiment 1 was indeed conditional in nature by comparing performance on conditional versus nonconditional versions of the task. Experiment 4 showed that PND19 and PND23 pups also were capable of performing the task when maze+mesh was the cue; however, the findings indicate that PND19 subjects do not use a conditional strategy to learn this task. The findings suggest postnatal ontogeny of conditional discrimination learning and underscore the importance of conditional cue salience, and of identifying task strategies, in developmental studies of conditional discrimination learning.

Contextual modulation of spatial discrimination reversal in developing rats.

Reversal of discrimination learning is influenced by manipulation of the training context. In adult and developing rats, contextual changes made between acquisition and reversal aid the learning of the new discrimination, possibly by serving to release proactive interference from the originally acquired discrimination (M. E. Bouton & D. C. Brooks, 1993; N. Spear, G. Smith, R. Bryan, & W. Gordon, 1980). The present study sought to examine this effect in an appetitive T-maze task, as a function of different contextual manipulations. Rats of three ages, Postnatal Day (PND) 19, PND23, and PND30, were tested for their ability to acquire and reverse a position habit in a T-maze. Contextual changes were made between acquisition and reversal sessions and consisted of one of three manipulations: (a) texture; the texture of the maze floor was changed via the addition or subtraction of wire mesh; (b) maze; subjects were reversed in a different maze that was identical in construction to the training maze, but differed in spatial location; (c) texture and maze; subjects were shifted to the new maze, the floor of which differed in texture from the training maze but was otherwise identical in construction. Results showed that the texture-maze combination was an effective aid to reversal learning at all ages tested. The texture alone, however, was not effective at any age. The maze alone also was an effective cue for reversal, but proved to have the greatest effect for PND30 subjects. During ontogeny, the contextual modulation of reversal learning is importantly influenced by the nature and the salience of the contextual cue.