هیپوتالاموس: جاده های متقاطع غدد و مقررات رفتاری در نظافت و خشونت

Abstract Anatomical and functional studies show that the hypothalamus is at the junction of mechanisms involved in the exploratory appraisal phase of behaviour and mechanisms involved in the execution of specific consummatory acts. However, the hypothalamus is also a crucial link in endocrine regulation. In natural settings it has been shown that behavioural challenges produce large and fast increases in circulating hormones such as testosterone, prolactin, corticotropin and corticosterone. The behavioural function and neural mechanisms of such fast neuroendocrine changes are not well understood. We suggest that behaviourally specific hypothalamic mechanisms, at the cross-roads of behavioural and endocrine regulation, play a role in such neuroendocrine changes. Mild stimulation of the hypothalamic aggressive area, produces stress levels of circulating prolactin, corticotropin, and corticosterone. Surprisingly luteinizing hormone does not change. This increase in stress hormones is due to the stimulation itself, and not caused by the stress of fighting. Similar increases in corticosterone are observed during electrical stimulation of the hypothalamic self-grooming area. The corticosterone response during self-grooming-evoking stimulation is negatively correlated with the amount of self-grooming observed, suggesting that circulating corticosterone exerts a negative feedback control on grooming. Earlier literature, and preliminary data form our laboratory, show that circulating corticosterone exerts a fast positive feedback control over brain mechanisms involved in aggressive behaviour. Such findings suggest that the hormonal responses caused by the activity of behaviourally specific areas of the hypothalamus may be part of a regulation mechanism involved in facilitating or inhibiting the very behavioural responses that can be evoked from those areas. We suggest that studying such mechanisms may provide a new approach to behavioural dysfunctions associated with endocrine disorders and stress.

Introduction The hypothalamus is a phylogenetically old structure that is crucially involved in many behavioural responses that are essential to survival. The distinctive characteristics of hypothalamic responses, and the underlying anatomical organisation, suggests that the hypothalamus is a crucial node where circuits involved in exploratory appraisal in behaviour, link up with circuits involved in the execution of specific consummatory responses 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. At the same time, many different endocrine and autonomic mechanisms are regulated in the hypothalamus. The presence of both behavioural and endocrine mechanisms in the hypothalamus suggests that there is a local functional link between endocrine and behavioural processes. In behaviour subserving homeostatic function, such as eating, drinking, maintaining salt balance, and thermoregulation, the advantages of functional relations between behavioural and endocrine mechanisms are evident. However, in hypothalamic behavioural responses such as aggression or self-grooming, no obvious homeostatic functions seems to be involved. Rather such responses constitute different kinds of reactions to external stressors 11, 12, 13, 14, 15 and 16. 1.1. Hypothalamic grooming and hypothalamic aggression Hypothalamic grooming closely resembles grooming under natural conditions, such as grooming following stressors, grooming as a reaction to a disturbance of the body surface, or as a preliminary to resting behaviour, it consists of licking the paws, washing movements over the head, and fur licking, and it generally proceeds in cephalo-caudal direction 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 and 21. However, the precise temporal pattern of hypothalamic grooming depends on the method of induction: electrical stimulation, local infusion of glutamate agonists, or neuropeptides 12, 13, 14, 15, 16, 17, 18, 20 and 21. Interestingly, scratching, a normal constituent of the care of the body surface [11], is absent in hypothalamic grooming. Hypothalamic aggression, closely resembles the most violent elements of aggressive behaviour observed under natural conditions, it consists of biting the dorsal surface of an opponent, and forceful kicking the body of the opponent either during a clinch fight, or while jumping in the direction of an opponent in an upright defensive position. The precise form of the attack depends on the behaviour and position of the opponent, and on the intensity of the stimulation. Increasing stimulation intensity generally activates the attack pattern in cephalo-caudal direction, from gentle bites to forcefull bites, accompanied by force-full hind paw kicks, delivered mid air during jumps or during clinch fights 19, 22, 23, 24, 25 and 26. Interestingly, sideways threat is absent 22 and 23or suppressed [26]during hypothalamic stimulation, but not during induction of hypothalamic attack by local infusion of picotoxin or bicuculline 27 and 28. 1.2. Hormones and hypothalamic responses In natural settings aggressive behaviour is accompanied by fast increases in prolactin, corticotropin, α-melanocyte stimulating hormone, β-endorphin, testosterone and corticosterone 29, 30, 31 and 32. Such hormonal responses allegedly help the organism to adapt to the stressors associated with the consequences of conflicts. Hypothalamic mechanisms have been implicated in such facilitation. Blood flow from the adrenals, and plasma catecholamine levels, increase following stimulation of hypothalamic areas involved in defense, flight and aggressive behaviour in the cat 33, 34, 35, 36, 37, 38, 39 and 40and rat [41]. However, there is also an influence in the reverse direction, from circulating hormones to the central nervous system [42]. Corticosterone facilitates clawing responses in copulation of the rough skin newt 43, 44, 45 and 46. Circulating hormones also influence central mechanisms involved in specific behavioural responses. Hypothalamic mechanisms have been implicated in the feedback of circulating hormones on central mechanisms. Estrogen, testosterone, FSH and LH facilitate or inhibit hypothalamic aggression in intact and gonadectomized, male and female cats [47]and rats [48]. Corticosterone injections immediately facilitate aggressive behaviour, in the rat, and antibodies against ACTH inhibit aggressive behaviour 49, 50 and 51. Moreover, infusions of cortisol into the anterior hypothalamus of the golden hamster facilitate aggressive behaviour 52 and 53. Such fast effects of stress hormones on brain mechanisms involved in aggressive behaviour may well be involved in the facilitating carry-over effect of a previous aggressive encounter on to subsequent aggression 54, 55, 56, 57 and 58. We suggest that fast facilitating effects of stress hormones on brain mechanisms involved in aggressive behaviour could also contribute to the escalation of violence in humans under stressful conditions. In this paper, we summarize what is known about the neural organization underlying hypothalamic responses, discuss the distinctive characteristics of the responses evoked, and demonstrate for the first time that a mild activation of the hypothalamic areas involved in specific behavioural responses is sufficient to evoke stress levels of prolactin, corticotropin, and corticosterone. Luteinizing hormone was studied because of the well known effects of testosterone on aggressive behaviour and hypothalamic aggression 3, 47 and 48. Corticotropine, and corticosterone were studied because of the fast aggression facilitating effects via hypothalamic mechanisms 52 and 53on territorial aggression 49 and 50. Moreover, deviant cortisol and prolactin responses to a serotonergic challenge have been observed in pathological hostility and impulse control in humans 59, 60, 61, 62 and 63. Similar findings have been reported for prolactin in monkeys [64].

. Results 4.1. Grooming area 4.1.1. Corticotropin Fig. 2(a) shows that stimulation of the grooming area at threshold intensity increased circulating corticotropin from about 0.02 to about 0.45 nmol/l. There is a significant overall difference (MANOVA, df=1, F=24.365, p<0.001) between stimulated rats (n=7) and unstimulated procedure controls (n=11). Time elapsed since the start of blood sampling had a significant effect on plasma corticotropin levels in the stimulated animals (MANOVA, df=6, F=23.3, p<0.001), but also in the control animals (MANOVA, df=6, F=15.4, p<0.001). Control and stimulation animals did not differ in basal corticotropin levels (p>0.05). Plasma corticotropin was significantly higher in the stimulated rats than the procedure controls at 15 and 30 min following the start of blood sampling (p<0.05). At all later moments after the start of blood sampling differences between stimulated rats and procedure controls are not significant (p>0.05). At 120 min corticotropin levels have almost returned to basal levels. 4.1.2. Corticosterone Fig. 2(b) shows that stimulation of the grooming area at threshold intensity increased circulating corticosterone from about 100 to about 500 nmol/l. During stimulation, plasma corticosterone levels between stimulated rats (n=7) and procedure controls (n=9) differ significantly (MANOVA, df=1, F=11.5, p=0.0014). However, it is clear that corticosterone levels in the stimulated group rises at start of the stimulation, while the corticosterone level in the procedure controls rises at later in time. Time elapsed since the start of sampling had a significant effect on plasma corticosterone both in the stimulated animals (MANOVA, df=6, F=5.4, p=0.004), and also (MANOVA; df=6, F=5.0, p=0.006) in the control animals. Control and stimulated animals did not differ in basal corticosterone levels (p>0.05). However, plasma corticosterone was significantly higher in the stimulated rats than the procedure controls at 15, and 30 following the start of blood sampling (p<0.05). At 45, 60, 90 and 120 min after the start of blood sampling there is no significant difference between stimulated rats and control rats (all ps>0.05), but corticosterone levels have not completely returned to the basel levels observed at the time of the first blood sampling. We have no data on prolactin and luteinizing hormone following stimulation of the grooming area. 4.2. Aggressive area 4.2.1. Corticotropin Fig. 2(c) shows that stimulation at threshold intensity increased circulating corticotropin (to 0.1 nmol/ml) from low basal, early light period levels. The overall difference between the stimulated (n=6), and the not stimulated group (n=4) is significant (MANOVA, df=1, F=26.818, p<0.001). In the stimulated rats the plasma corticotropin changed in time following the taking of the first blood sample (MANOVA, df=5, F=11.8, p<0.001). There was no time-dependent effect of corticotropin in the procedure controls. Procedure controls and stimulated rats did not differ in basal corticotropin levels, but stimulated rats had higher corticotropin levels at 15 and 30 min following the start of stimulation (p<0.01 p<0.005, respectively). At 45, 60 and 120 min following the start of the stimulation, differences between stimulated and not-stimulated rats are not significant (p>0.05) as corticotropin levels in the stimulated rats return to baseline. 4.2.2. Corticosterone Fig. 2(d) shows that stimulation at threshold intensity increased circulating corticosterone from low levels (about 300 nmol/l) to high stress levels (about 1100 nmol/l). No comparable rise was observed in the procedure controls. The overall difference between the stimulated rats (n=8), and the procedure controls (n=4) is significant (MANOVA, df=1, F=138.9, p<0.001). In the stimulated animals, but not in the procedure controls, plasma corticosterone changed significantly over time from the moment of the first blood sampling (MANOVA, df=5, F=10.1, p<0.001). Procedure controls and stimulated rats did not differ in basal corticosterone levels. However stimulated rats had significantly higher corticosterone at 15, 30, 45 and 60 min following the start of stimulation (p<0.02, 0.02, 0.02 and 0.05, respectively). At 120 min corticosterone levels in stimulated animals had returned to baseline and no differences with procedure controls were in evidence (p>0.05). 4.2.3. Prolactin Fig. 2(e) shows that stimulation at threshold intensity increased circulating prolactin from about 2 μg/l to about 40 μ/l There is a significant overall difference between groups (MANOVA, df=1, F=8.5, p<0.001). In the stimulated animals (n=12), plasma prolactin changed significantly over time (MANOVA, df=5, F=8.59, p<0.001). There is no time dependent effect in the procedure controls (n=7). Control and stimulation animals did not differ in basal prolactin levels (p>0.05) However, plasma prolactin was significantly higher in the stimulated rats than the procedure controls at 15, 30 and 45 min following the start of stimulation (p<0.01, in all cases). At 60 and 120 min after the start of stimulation there are no significant differences between stimulated rats and control rats (p>0.05), and prolactin levels have returned to basal levels. 4.2.4. LH Fig. 2(d) shows that luteinizing hormone levels do not change following 30 min stimulation in the hypothalamic aggressive area (n=6). There is no significant overall effect of treatment (MANOVA; df=1, F=0.68, p=0.44). The time course of LH plasma levels does not differ significantly between the control (n=3) and the stimulated rats (MANOVA; df=5, F=1.03, p=0.418). One rat in the control group and one rat in the stimulated group showed a short elevation of LH, which seemed unrelated to the 30 min stimulation period. 4.3. Comparison hormone responses grooming and aggression area As can be seen in Fig. 2(a, c) the corticotropin response to stimulation in the grooming area is significantly larger than the corticotropin response to stimulation in the aggression area (MANOVA, df=1, F=14.3, p<0.001). However, as can be seen in Fig. 2(b,d) the corticosterone response to stimulation in the grooming area is significantly smaller than the corticosterone responses to stimulation (MANOVA, df=1, F=13.2, p<0.001). The differences in corticotropin levels are mainly due to time points 15 and 30 min (p<0.005), i.e. during stimulation. The differences in corticosterone are longer lasting and are significant for 15–60 min following the onset of stimulation (p<0.02, in all cases).