Kim L. Huhman

Conditioned defeat in male and female Syrian hamsters

A brief exposure to social defeat in male Syrian hamsters (Mesocricetus auratus) leads to profound changes in the subsequent agonistic behavior exhibited by the defeated animals. Following defeat in the home cage of an aggressive conspecific, male hamsters will subsequently fail to defend their home territory even if the intruder is a smaller, nonaggressive male. This phenomenon has been called conditioned defeat. In Experiment 1, we examined the duration of conditioned defeat by repeatedly testing (every 3-5 days) defeated hamsters with a nonaggressive intruder. We found that conditioned defeat occurs in all defeated male hamsters and persists for a prolonged period of time (at least 33 days) in the majority of male hamsters tested despite the fact that these animals are never attacked by the nonaggressive intruders. In Experiment 2, we examined whether conditioned defeat could be induced in female Syrian hamsters. While conditioned defeat occurred in some females, they displayed only low levels of submissive/defensive behavior and, in contrast to males, the conditioned defeat response did not persist beyond the first test. These results suggest that in male hamsters conditioned defeat is a profound, persistent behavioral change characterized by a total absence of territorial aggression and by the frequent display of submissive and defensive behaviors. Conversely, social defeat in female hamsters does not appear to induce long-term behavioral changes. Finally, in Experiment 3, we determined that plasma adrenocorticotropin-like immunoreactivity increases in females following social defeat in a manner similar to that seen in males, suggesting that the disparate behavioral reactions of males and females are not due to sex differences in the release of, or response to, plasma adrenocorticotropin.

Social conflict models: Can they inform us about human psychopathology?

Social conflict models have been proposed as a powerful way to investigate basic questions of how brain and behavior are altered by social experience. Social defeat, in particular, appears to be a major stressor for most species, and in humans, this stressor is thought to play an important role in the onset of a variety of psychiatric disorders including depression and post-traumatic stress disorder. Aggressive experience, on the other hand, may promote disorders involving inappropriate aggression and violence. Current research using animal models of social conflict involves multiple levels of analysis from genetic and molecular to systems and overt behavior. This review briefly examines a variety of these animal models of social conflict in order to assess whether they are useful for advancing our understanding of how experience can shape brain and behavior and for translating this information so that we have the potential to improve the quality of life of individuals with mental illness and behavioral disorders.

Neuropeptide Y microinjected into the suprachiasmatic region phase shifts circadian rhythms in constant darkness.

The geniculohypothalamic tract (GHT) is a projection from the intergeniculate leaflet to the suprachiasmatic nucleus (SCN). The GHT exhibits neuropeptide Y (NPY) immunoreactivity and appears to communicate photic information to the SCN. Microinjection of NPY into the SCN has been found to phase shift circadian rhythms of hamsters housed in constant light in a manner similar to the phase shifts produced by pulses of darkness or triazolam injections. In the present study, NPY was injected into the SCN of Syrian hamsters housed in constant darkness and was found to produce phase shifts similar to those seen in hamsters housed in constant light. Microinjections were not followed by wheel running during the subjective day (the time when NPY microinjections are followed by significant phase advances). These data suggest that NPY produces phase shifts by some mechanism other than by inducing wheel running or by inhibiting the response of SCN neurons to light and supports a role for NPY in nonphotic shifting of the circadian clock.

Short-day increases in aggression are inversely related to circulating testosterone concentrations in male Siberian hamsters (Phodopus sungorus).

Many nontropical rodent species display seasonal changes in both physiology and behavior that occur primarily in response to changes in photoperiod. Short-day reductions in reproduction are due, in part, to reductions in gonadal steroid hormones. In addition, gonadal steroids, primarily testosterone (T), have been implicated in aggression in many mammalian species. Some species, however, display increased aggression in short days despite basal circulating concentrations of T. The goal of the present studies was to test the effects of photoperiod on aggression in male Siberian hamsters (Phodopus sungorus) and to determine the role of T in mediating photoperiodic changes in aggression. In Experiment 1, hamsters were housed in long and short days for either 10 or 20 weeks and aggression was determined using a resident-intruder model. Hamsters housed in short days for 10 weeks underwent gonadal regression and displayed increased aggression compared to long-day-housed animals. Prolonged maintenance in short days (i.e., 20 weeks), however, led to gonadal recrudescence and reduced aggression. In Experiment 2, hamsters were housed in long and short days for 10 weeks. Half of the short-day-housed animals were implanted with capsules containing T whereas the remaining animals received empty capsules. In addition, half of the long-day-housed animals were castrated whereas the remaining animals received sham surgeries. Short-day control hamsters displayed increased aggression compared to either castrated or intact long-day-housed animals. Short-day-housed T treated hamsters, however, did not differ in aggression from long-day-housed animals. Collectively, these results confirm previous findings of increased aggression in short-day-housed hamsters and suggest that short-day-induced increases in aggression are inversely related to gonadal steroid hormones.

Serotonergic regulation of circadian rhythms in Syrian hamsters

This study investigated the effects of (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaline hydrobromide (8-OH-DPAT) on circadian rhythms in Syrian hamsters. Systemic administration of 8-OH-DPAT (0.75 mg in 150 microl saline) at circadian time 7 produced phase advances in the circadian activity rhythm. These 8-OH-DPAT-induced phase advances were blocked by microinjection of bicuculline (166 ng, 200 nl) into the suprachiasmatic nucleus, suggesting that GABAergic activity in the suprachiasmatic nucleus mediates the phase shifts produced by systemic injections of 8-OH-DPAT. Microinjection of 8-OH-DPAT (1 microg, 200 nl) or serotonin (0.7 microg, 200 nl) directly into the suprachiasmatic nucleus did not induce phase shifts at circadian time 7, suggesting that the phase shifting effects of systemic injection of 8-OH-DPAT are mediated outside the suprachiasmatic nucleus. To examine possible sites of action of 8-OH-DPAT, 8-OH-DPAT (0.5 microg (100 nl) or 1.0 microg (200 nl)) was microinjected into the intergeniculate leaflet, dorsal raphe nuclei, and the median raphe nucleus at circadian time 7. Significant phase advances were observed after microinjection into the dorsal raphe and median raphe but not the intergeniculate leaflet. These results support the hypothesis that systemic injection of serotonergic agonists can alter circadian rhythms via action in the midbrain raphe nucleus, and that the phase shifts induced by microinjection of 8-OH-DPAT into the raphe nuclei are mediated by a neurotransmitter other than serotonin within the suprachiasmatic nucleus.

GABA(A) and GABA(B) agonists and antagonists alter the phase-shifting effects of light when microinjected into the suprachiasmatic region.

GABAergic drugs have profound effects on the regulation of circadian rhythms. The present study evaluated the effects of microinjections of GABAergic drugs into the suprachiasmatic region in hamsters on phase shifts induced by light and by microinjection of a cocktail containing vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI) and gastrin-releasing peptide (GRP). The phase-advancing effects of light at circadian time (CT) 19 were significantly reduced by microinjection of GABA(A) or GABA(B) agonists into the SCN, but were not altered by microinjection of GABA(A) or GABA(B) antagonists. Microinjection of a GABA(B) agonist also reduced the phase-delaying effects of light at CT 13.5-14 while a GABA(B) antagonist increased the phase delays caused by light. Neither GABA(B) drug altered the phase delays produced by microinjection of a peptide cocktail containing VIP, PHI, GRP. These data indicate that changes in GABA(A) or GABA(B) activity within the SCN can alter the phase-shifting effects of light on circadian rhythms and support a role for GABA in gating photic input to the circadian clock.

Activation of GABAA receptors in the amygdala blocks the acquisition and expression of conditioned defeat in Syrian hamsters

Social defeat is a powerful experience that often leads to drastic physiological and behavioral changes in many animal species. An example of such a change is conditioned defeat in Syrian hamsters. The neurophysiological mechanisms that underlie such changes are not yet fully understood, however, there is evidence that the amygdala plays an essential role in behavioral and emotional responses to a variety of stressors. The goal of the present study was to determine whether GABAergic neurotransmission in the amygdala is a critical component of conditioned defeat in male Syrian hamsters. Experiment 1 examined whether infusion of the GABA(A) receptor agonist, muscimol (0.0, 4.4, 8.8 nmol), into the amygdala would block the acquisition of conditioned defeat. Experiment 2 examined whether infusion of muscimol into the amygdala prior to testing would block expression of conditioned defeat. Submissive behavior during testing was significantly reduced in animals receiving infusions of muscimol immediately prior to initial defeat training. Animals that received infusions of muscimol immediately prior to being tested with a non-aggressive intruder also displayed significantly less submissive behavior than did animals receiving vehicle control. These data indicate that infusion of muscimol into the amygdala can block the acquisition and expression of conditioned defeat, a finding that indicates that GABAergic neurotransmission within the amygdala is involved in the acquisition and expression of fear or stress-induced behavioral changes. This is the first evidence indicating that the neural circuits involved in Pavlovian fear conditioning are also involved in more ethologically-relevant models examining stress-related behavioral plasticity.

Involvement of Central Amygdalar and Bed Nucleus of the Stria Terminalis Corticotropin-Releasing Factor in Behavioral Responses to Social Defeat

The authors investigated whether corticotropin-releasing factor (CRF) within the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST) is a critical component of the neural circuitry mediating conditioned defeat. In this model, hamsters that have experienced social defeat subsequently display only submissive-defensive agonistic behavior instead of territorial aggression. Conditioned defeat was significantly reduced following infusion of the CRF receptor antagonist D-Phe CRF((12-41)) into the BNST but not into the CeA. In another experiment, hamsters given unilateral lesions of the CeA and infusions of D-Phe CRF((12-41)) into the contralateral BNST displayed significantly less submissive behavior than did controls. These data suggest that CRF acts within a neural circuit that includes the amygdala and the BNST to modulate agonistic behavior following social defeat.

Neuropeptide Y phase shifts circadian rhythms in vivo via a Y2 receptor.

NEUROPEPTIDE Y (NPY) injected into the suprachiasmatic region 6 h before the onset of locomotor activity produces phase advances in circadian rhythms. The present study investigated whether the phase advances produced by NPY in Syrian hamsters are mediated by a Y1- or Y2-like NPY receptor by comparing the phase advancing effects of the Y1 agonist, [Leu31,Pro34]NPY, and the Y2 agonist, NPY(3–36), following their injection into the suprachiasmatic region. Microinjection of the Y2 agonist produced phase advances that were significantly greater than those produced by the microinjection of the Y1 agonist. These data support the hypothesis that the phase advancing effects of NPY in the suprachiasmatic region are mediated by a Y2-like NPY receptor, similar to results found in vitro.

Oxytocin Inhibits Aggression in Female Syrian Hamsters

Dominant subordinate relationships are formed as the result of social conflict and are maintained at least in part by communication. At this time, little is known about the neural mechanisms that are responsible for coordinating the social behaviours (e.g. aggression) that occur in association with the formation and maintenance of these relationships. The purpose of the present study was to investigate the role of oxytocin (OXT) within the medial preoptic anterior hypothalamic continuum (MPOA‐AH) in the control of aggression in female hamsters. OXT injected into the MPOA‐AH immediately before testing significantly reduced the duration of aggression in a dose‐dependent manner. Injection of an OXT antagonist 30 min before testing significantly increased the duration of aggression. In contrast, the duration of aggression was not altered when hamsters were tested either 30 min after injection of OXT or immediately following injection of an OXT‐antagonist. These data support the hypothesis that OXT release within the MPOA‐AH regulates social behaviours important in the formation and maintenance of dominant subordinate relationships in female hamsters.