Henry Edinger

The organization of the hypothalamic pathways mediating affective defense behavior in the cat

The purpose of this study was to describe the hypothalamic pathways which mediate affective defense in the cat utilizing the methods of [14C]2-deoxyglucose (2-DG) and [3H]leucine radioautography in concert with the technique of electrical brain stimulation. The feline affective defense response, characterized by pupillary dilatation, piloerection, ear retraction, hissing, growling and striking with the forepaws, was elicited consistently by stimulation of sites within the ventromedial hypothalamus and anterior aspect of the medial hypothalamus. In one series of experiments, 2-DG autoradiography was employed to describe the brain regions activated following stimulation of sites in the region of the ventromedial hypothalamus from which affective defense had been elicited. Ventromedial hypothalamic stimulation produced activation primarily in forebrain regions situated rostral to the level of the stimulating electrode. These structures included principally the anteromedial hypothalamus and medial preoptic area, as well as the bed nuclei of the stria terminalis and anterior commissure, diagonal band and lateral septal area. The caudal extent of activation included only the dorsal and perifornical hypothalamus at the level of the stimulation site. In a second series of experiments, affective defense sites in the anteromedial hypothalamus were stimulated and the regional distribution of 2-DG label was identified. In contrast to the results obtained from ventromedial hypothalamic stimulation, these experiments revealed a marked descending distribution of label within the posterior hypothalamus, midbrain central gray and ventral tegmental area. Results obtained from studies in which tritiated amino acids were injected into affective defense sites in both the ventromedial nucleus and anteromedial hypothalamus confirmed the general findings observed with 2-DG autoradiography. From these observations, we have concluded that the organization of the pathway mediating affective defense behavior from the ventromedial hypothalamus to the midbrain involves an initial synapse within the region of the anteromedial hypothalamus and a second synapse in the midbrain central gray substance. The significance of the anteromedial hypothalamus for the expression of affective defense behavior was considered in the Discussion.

The role of the anterior hypothalamus in affective defense behavior elicited from the ventromedial hypothalamus of the cat

In the preceding paper a hypothalamic circuit subserving feline affective defense behavior was described. This circuit included an ascending component from the ventromedial nucleus to the anterior hypothalamus and a descending component from the anterior hypothalamus to the midbrain central gray substance. The present study was undertaken to test the hypothesis that the anterior hypothalamus plays a central role in the organization of this functional pathway. In the first part of this study, dual stimulation methods were utilized to demonstrate that concurrent stimulation of the ventromedial hypothalamus facilitates the occurrence of affective defense responses elicited from the anterior hypothalamus. In the second part of the study, lesions placed in the anterior hypothalamus significantly increased the latency and threshold current for affective defense responses elicited from the ventromedial hypothalamus. [14C]2-deoxyglucose autoradiography confirmed the fact that anterior hypothalamic lesions effective in blocking affective defense were placed in regions where the vast majority of ventromedial hypothalamic fibers terminate. In contrast, lesions which had little or no effect upon the latency or threshold for affective defense elicited from the ventromedial hypothalamus appeared to leave intact the connections from the ventromedial to the anterior hypothalamus. These findings are consistent with the proposed intrahypothalamic anatomical substrate subserving affective defense behavior described in the preceding paper.

The origin of the afferent supply to the mediodorsal thalamic nucleus: Enhancement of HRP transport by selective lesions

Abstract This experiment attempted to identify the cell bodies of origin of axons in the forebrain which supply the mediodorsal thalamic nucleus (MD). Injections of horseradish peroxidase (HRP) were placed into MD in 60 rats. Survival times varied from 1–4 days. Following injections placed into different portions of MD, HRP positively labeled cells were observed in a variety of forebrain structures which lie rostral to the injection sites. Discrete injections of HRP placed into the midline of MD labeled cells situated exclusively in the extreme ventromedial aspect of central levels of the reticular nucleus. HRP injections which included anterior levels of MD labeled cells situated principally in layers V–VI of the sulcal prefrontal cortex, while injections which involved more posterior and lateral portions of MD labeled cells in the deepest layers of the dorsomedial prefrontal cortex. Injections of this region of MD also labeled cells in adjacent portions of the deepest layers of anterior cingulate gyrus, polymorphic cell layer of prepyriform cortex and olfactory tubercle and sites immediately lateral to the vertical limb of the diagonal band and dorsal to its horizontal limb. Positively labeled cells were observed in the cortical, medial, basolateral and basomedial amygdaloid nuclei and adjacent pyriform cortex only when ablations of prefrontal cortex preceded HRP injections of MD. This findings indicates that lesions of the prefrontal cortex dramatically enhance the HRP labeling process in the amygdala and suggests the possibility that the technique involving the placement of selective lesions may be used to advangate in other anatomical systems which receive multiple inputs from widely distributed sources.

Effects of amygdaloid stimulation upon trigeminal sensory fields of the LIP that are established during hypothalamically-elicited quiet biting attack in the cat

An experiment was performed in order to determine the role of the amygdala and surrounding cortex in quiet biting attack elicited from electrical stimulation of the hypothalamus. Stimulation of basal, cortical, and anterior amygdala as well as pyriform cortex and parahippocampal gyrus resulted in a suppression of the attack response and in a constriction of trigeminal sensory fields that are established during hypothalamic stimulation. Stimulation of lateral and central amygdala resulted in a facilitation of the quiet biting attack response and an expansion of the trigeminal sensory fields, and a decreased latency for the occurrence of jaw opening when the sensory field was held constant. These studies suggest that the amygdala modulated quiet biting attack behavior generated by hypothalamic stimulation at least, in part, by virtue of its control over sensory fields.

Differential fornix ablations and the circadian rhythmicity of adrenal corticosteroid secretion

Suction ablations of the medial or lateral fornix were performed in order to transect selectively the medial corticohypothalamic tract (mcht) which originates in the anteroventral subiculum and travels in the lateral fornix terminating in the basal hypothalamus. The circadian rhythmicity of plasma adrenal corticosteroid levels was assessed in individual animals 1--2 weeks postoperatively. Ablation of the lateral fornix disrupted the periodicity of corticosteroid secretion which is normally synchronized with the light--dark cycle, whereas medial fornix ablation or neocortical ablation caused no such disruption. Group mean levels of plasma adrenal corticoids were higher in the lateral fornix-ablated animals than in the medial fornix-ablated, neocortically ablated, or intact control animals. These findings suggest that the anteroventral subiculum is important in the regulation of adrenal corticosteroid rhythmicity, and that it exerts an inhibitory influence upon corticosteroid release.

Effects of electrical stimulation of the lateral aspect of the prefrontal cortex upon attack behavior in cats

Abstract An experiment was performed to determine the role of the lateral aspect of the prefrontal cortex upon quiet biting attack behavior elicited from the hypothalamus in the cat. The results of this experiment indicate that stimulation of 19 of 28 electrode sites sampled in the lateral prefrontal cortex produced a statistically significant inhibition of attack behavior elicited from the hypothalamus of the ipsilateral side. Stimulation of sites in the prefrontal cortex on the side contralateral to the hypothalamus from which attack was elicited had no effect upon this response. No systematic effect of prefrontal stimulation upon flight behavior was observed. Anatomical studies suggest that the lateral prefrontal cortex may inhibit attack behavior by modulating neurons in either the mediodorsal thalamic nucleus or ventral tegmental area.

Effects of experimental temporal lobe seizures upon hypothalamically elicited aggressive behavior in the cat

An experiment was performed in order to determine the effects of temporal lobe seizures upon hypothalamically elicited aggressive behavior in the cat. Seizures were induced by electrical stimulation of the pyriform cortex or those subnuclei of the amygdala which had previously been shown to modulate aggressive responses at subseizure current levels. The results clearly indicate that a significant modification of affective defense thresholds following seizures was a direct function of the locus of stimulation. Specifically, seizures generated from the pyriform cortex and medial aspects of the amygdala (sites associated with prior facilitation of affective defense as determined by subseizure electrical stimulation) were followed by a reduction in threshold for this response. In contrast, an elevation in affective defense thresholds occurred when seizures were generated from the central or lateral nuclei of the amygdala (sites associated with prior suppression of affective defense as determined by subseizure electrical stimulation). The primary pathway utilized in the facilitation of affective defense appears to involve the stria terminalis, its bed nucleus, and the anterior medial hypothalamus. Preliminary data suggest that seizures generated from the pyriform cortex or amygdala can also modify quiet biting attack behavior, but in a manner opposite to that demonstrated for affective defense.

D2 dopamine receptor-mediated mechanisms in the medial preoptic-anterior hypothalamus regulate affective defense behavior in the cat

The role of the dopaminergic innervation of the medial preoptic-anterior hypothalamus (mPO-AH) in regulating the expression of affective defense behavior in the cat has been investigated in the present study. Feline affective defense behavior, characterized mainly by autonomic arousal, ear retraction, growling, hissing and paw striking, was elicited by electrical stimulation of the ventromedial hypothalamic nucleus (VMH). Following the establishment of a stable threshold current for eliciting the hissing response of the behavior, the effect of injecting various DAergic agonists and antagonists into the mPO-AH on the hissing threshold was determined. The microinjection of the non-selective DA agonist apomorphine (0.03, 0.16, 0.33, 0.66, 1.56 and 3.3 nmol) into the mPO-AH facilitated hissing in a time- and dose-dependent manner. This effect was mimicked by the D2-selective agonist LY 171555 (0.2 and 1.0 nmol) but not by the D1-selective agonist SKF 38393 (1.7 and 17 nmol), and was blocked by the non-selective and the D2-selective antagonists haloperidol (1.3 nmol) and sulpiride (14.5 nmol), respectively. The injection of the D1-selective antagonist SCH 23390 (0.3 nmol), however, did not inhibit apomorphine-induced facilitation of hissing. In addition, the injection of haloperidol (1.3 nmol) and sulpiride (14.5 nmol), but not SCH 23390 (0.3 nmol), alone inhibited the behavior. It was therefore concluded that dopaminergic stimulation of the mPO-AH may facilitate the expression of affective defense behavior in the cat via a D2 receptor-mediated mechanism. The physiological significance of this effect and the interaction between dopaminergic, noradrenergic and serotonergic innervation of the mPO-AH in modulating the expression of affective defense behavior in response to threatening stimuli are discussed.

A [14C]2-Deoxyglucose analysis of the functional neural pathways of the limbic forebrain in the rat. III. The hippocampal formation

The regions metabolically activated in the rat brain following focal electrical stimulation of various components of the hippocampal formation were identified with the use of [14C]2-deoxyglucose (2-DG) autoradiography. The results of these experiments, conducted in the rat, showed that in the absence of elicited afterdischarge activity, stimulation of either the CA1 or CA3 field of the dorsal hippocampus resulted in bilateral metabolic activation of only the dorsal hippocampus as well as of a relatively restricted region within the dorsomedial aspect of the lateral septal nucleus, bilaterally. In contrast, stimulation of either the CA1 or CA3 field of the ventral hippocampus resulted in bilateral activation of the ventral hippocampus and no region of the dorsal hippocampus. Following such stimulation, the lateral septal nucleus was also labeled bilaterally, but the activated regions were situated in a position ventrolateral to those resulting from stimulation at dorsal levels. Stimulation of the subicular cortex, in contrast, resulted in only ipsilateral activation of the hippocampal formation and lateral septal nucleus. Further rostral levels of the lateral septal nucleus were noted to be activated following stimulation of subicular cortex as compared to stimulation of the cornu Ammonis. The hypothalamus was directly activated by two pathways, the postcommissural fornix and the medial corticohypothalamic tract. Following stimulation at dorsal and posterior levels of CA1 and the subiculum, the mammillary bodies were demonstrably labeled by input from the postcommissural fornix. Regions of the medial hypothalamus were activated via the medial corticohypothalamic tract following stimulation of the ventral subiculum. The amygdala, stria terminalis and its bed nucleus were also shown to be demonstrably activated following stimulation of the ventral subiculum, ventral CAl field and posterior prosubiculum. This pathway may represent an additional route by which hippocampal modulation may indirectly modulate hypothalamic function. The presence of elicited afterdischarges resulted in more extensive patterns of metabolic labeling within the hippocampal formation and lateral septal nuclei as compared to experiments in which afterdischarges were not elicited. The extent of the demonstrable labeling, both within, and extrinsic to the hippocampal formation appeared to be a function of the duration and severity of the elicited seizure discharge. Additional structures which were demonstrably labeled following the elicitation of seizure activity include the entorhinal cortex-prepyriform area, amygdala, substantia innominata, putamen, substantia nigra, olfactory and prefrontal cortices and medial thalamic nuclei.

Role of the limbic system in hypothalamically elicited attack behavior

The present review summarizes our research findings concerning the role of the limbic system in hypothalamically-elicited aggression in the cat. Utilizing a dual-stimulation procedure, our results indicate that much of the limbic system suppresses quiet biting attack behavior. The most potent inhibitory effects were obtained from the basomedial amygdala and the prefrontal cortex. Other structures displaying suppression of attack following electrical stimulation include the dorsal hippocampus, pyriform cortex, lateral septal nucleus, lateral aspect of substantia innominata, and anterior cingulate gyrus. Sites producing facilitation of attack include the ventral hippocampus, far lateral aspect of the lateral septal nucleus, medial aspect of the substantia innominata, and lateral amygdaloid nucleus. Anatomical studies suggest that the medial forebrain bundle and stria terminalis are utilized by limbic structures to provide direct modulation of the hypothalamus while the substantia innominata, mediodorsal thalamic nucleus and bed nucleus of the stria terminalis contain important interneurons in the control of quiet biting attack. Further studies indicate that the amygdala, ventral hippocampus, and substantia innominata may control aggressive behavior by modulating the trigeminal sensory components of the attack response.