Allan Siegel

Efferent connections of the septal area in the rat: An analysis utilizing retrograde and anterograde transport methods

Experiments were performed by either retrograde (horseradish peroxidase histochemistry) or anterograde ([3H]leucine radioautography) transport methods to determine the efferent connections of the septum in the rat. It was observed that the dorsal septum projects to the lateral preoptic area, lateral hypothalamus, periventricular hypothalamus and midline thalamus. Fibers from the ventral half of the septum project topographically to the hippocampal formation, thalamus, hypothalamus and midbrain. Specifically, neurons located along the midline in the vertical limb of the diagonal band project through the dorsal fornix to all CA fields of the dorsal hippo campus and adjacent subicular cortex. Other fibers from this region project through the stria medullaris to the medial habenular nucleus and anteromedial nuclhe pars posterior of the medial mammillary nucleus. Cells located immediately lateral to the midline in the vertical limb of the diagonal band project through the medial part of the fimbria to all CA fields of the posterior hippocampus and adjacent subicular cortex. Other fibers which originate from this region project through the stria medullaris to both the medial and lateral habenular nuclei and the paratenial nucleus of the thalamus, and through the medial forebrain bundle to the pars posterior of the medial mammillary nucleus. Cells located in the intermediolateral septum project through the lateral part of the fimbria to all CA fields of the ventral hippocampus and adjacent subicular and entorhinal cortices. These cells also send fibers through the stria medullaris to the lateral habenular nucleus and mediodorsal thalamic nucleus. Other axons arising from these cells descend through the medial forebrain bundle to terminate in a region dorsal to the interpeduncular nucleus. Fibers from the most lateral part of the ventrl septum (i.e., bed nucleus of the anterior commissure) project through the stria terminalis to the ventral subiculum. In addition, cells located in the horizontal limb of the diagonal band project massively to the pars posterior of the medial mammillary nucleus and the ventral tegmental area, and amygdala.

Efferent connections of the hippocampal formation in the rat

In this investigation the projections of the hippocampal formation to the septal area and hypothalamus were studied in the rat with the combined use of 3H-amino acid radioautography and horseradish peroxidase histochemistry. The results indicate that all of the fibers which project to the hypothalamus and the majority of fibers which project to the septum arise from the subicular cortex and not from hippocampal pyramidal cells. The projection to both of these areas are topographically organized along the longitudinal axis of the hippocampal formation. Specifically, fibers from subicular cortical cells situated at the septal end of the hippocampal formation which project through the medial part of the dorsal fornix terminate in the dorsomedial quadrant of the lateral septal nucleus and in the dorsal portion of the pars posterior of the medial mammillary nucleus. Fibers from progressively more posteroventral levels of the hippocampal formation which project through more lateral portions of the dorsal fornix and fimbria terminate in progressively lateral and ventral quadrants of the lateral septal nucleus and in progressively more ventral portions of the pars posterior. Concerning the specific origin of the fornix system, fibers from only the prosubiculum and subiculum project through both the pre- and postcommissural fornix. Hippocampal pyramidal cells from all CA fields have a restricted projection through the precommissural fornix and terminate in the caudal half of the septum while the presubiculum projects solely through the postcommissural fornix. The medial corticohypothalamic tract (MCHT) was found to arise from cells located in anterior ventral levels of the subicular cortex. Fibers from this tract appeared to be distributed throughout the pericellular region of the entire ventromedial extent of the hypothalamus from the level of the suprachiasmatic nucleus through the level of the medial mammillary nucleus. In this way, the mammillary bodies receive input from the subicular cortex via two routes: the descending column of the fornix and the MCHT.

Neuropharmacology of brain-stimulation-evoked aggression.

Evidence is reviewed concerning the brain areas and neurotransmitters involved in aggressive behavior in the cat and rodent. In the cat, two distinct neural circuits involving the hypothalamus and PAG subserve two different kinds of aggression: defensive rage and predatory (quiet-biting) attack. The roles played by the neurotransmitters serotonin, GABA, glutamate, opioids, cholecystokinin, substance P, norepinephrine, dopamine, and acetylcholine in the modulation and expression of aggression are discussed. For the rat, a single area, largely coincident with the intermediate hypothalamic area, is crucial for the expression of attack; variations in the rat attack response in natural settings are due largely to environmental variables. Experimental evidence emphasizing the roles of serotonin and GABA in modulating hypothalamically evoked attack in the rat is discussed. It is concluded that significant progress has been made concerning our knowledge of the circuitry underlying the neural basis of aggression. Although new and important insights have been made concerning neurotransmitter regulation of aggressive behavior, wide gaps in our knowledge remain.

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.

A [14C]2-deoxyglucose analysis of the functional neural pathways of the limbic forebrain in the rat. V: The septal area

Abstract In an attempt to further characterize the nature of the functional organization of the amygdala, patterns of uptake of [14C]2-deoxyglucose (2-DG) were assessed following electrical stimulation of various sites within the amygdala and associated structures in the rat. The experimental paradigm consisted of electrical brain stimulation delivered continuously for periods of 30 s on and 30 s off for 45 min following injection of 2-DG. Brains were removed and processed for autoradiography. It was noted that a specificity existed regarding nuclei, which when stimulated, resulted in demonstrable metabolic activation of the hypothalamus. Amygdaloid structures producing such activation included the medial, cortical, and basomedial nuclei, and the amygdalo-hippocampal area. Stimulation of these nuclear regions differentially activated areas within the hypothalamus. Stimulation of the medial and cortical nuclei effectively labeled fibers supplying the ventromedial nucleus. Stimulation of the amygdalo hippocampal area activated fibers which innervated the medial preoptic region. In contrast, activated fibers supplying the ventrolateral hypothalamus were present following stimulation of the basomedial nucleus. Activated fibers were observed in the lateral region of the medial forebrain bundle following stimulation of the central nucleus. Since these fibers could be followed directly into the substantia nigra, it was not possible to determine the extent to which they may have terminated within the lateral hypothalamus. Stimulation of other regions of the amygdala produced no demonstrable activation of any region of hypothalamus. The overall patterns of subcortical activation following stimulation of amygdaloid nuclei revealed the presence of considerable quantities of labeled fibers within the bed nucleus of the stria terminalis and substantia innominata. In addition, stimulation of the bed nucleus activated fibers which predominantly supply the ventromedial hypothalamus while stimulation of the substantia innominata activated fibers which supply the lateral hypothalamus. These data, taken collectively with previous anatomical data, suggest the likelihood that these two regions may serve as important relays through which much of the amygdala can communicate with the hypothalamus. An analysis was also made of the distribution of labeled fibers following the generation of seizure activity induced by focal injections of penicillin placed into various regions of amygdala. The data suggest that the pathways involved in the manifestation of a given induced seizure follow the known routes of axons, either arising from or passing through the structure associated with the seizure focus. While the activation pattern associated with focal seizures induced by the placement of penicillin into the basal nuclear complex appeared to be limited to first-order neurons, the patterns associated with seizures induced from the posterior cortical nucleus reflected the additional activation of second and third-order neurons of the hippocampal-septal system.

Evidence that substance P is utilized in medial amygdaloid facilitation of defensive rage behavior in the cat

The present study was designed to test the hypothesis that a major excitatory mechanism for the expression of feline defensive rage behavior involves the medial nucleus of the amygdala which utilizes substance P as a neurotransmitter in a direct output pathway that supplies the medial hypothalamus. In phase I of the experiment, stimulating electrodes were implanted into the medial amygdala and cannula electrodes were implanted into the medial and lateral hypothalamus from which defensive rage and predatory attack behavior could be elicited by electrical stimulation, respectively. Response latencies for defensive rage were significantly lowered after dual stimulation of the medial amygdala and medial hypothalamus relative to single stimulation of the medial hypothalamus alone. In phase II, dose- and time-dependent decreases in medial amygdaloid-induced facilitation of defensive rage were observed after the i.p. administration of the NK1 antagonist, CP-96,345 (0.05, 2 and 4 mg/kg). In phase III of the study, the effects of microinjections of CP-96,345 placed directly into defensive rage sites within the medial hypothalamus (0.05, 0.5 and 2.5 nmol) upon medial amygdaloid modulation of this response were assessed. Again, intracerebral administration of this antagonist blocked the facilitatory effects of medial amygdaloid-induced facilitation of defensive rage in a manner parallel to that observed with peripheral administration of the NK1 antagonist. The results suggest that the medial amygdala facilitates defensive rage by acting through a substance P mechanism at the level of the medial hypothalamus. Other experiments revealed that peripheral administration of the NK1 antagonist: (1) had little upon the latency or threshold for elicitation of defensive rage, suggesting that the medial amygdaloid-substance P facilitatory mechanism acts in a phasic rather than tonic manner; and (2) also blocks the suppressive effects of medial amygdaloid stimulation upon predatory attack behavior elicited from the lateral hypothalamus. The latter finding suggest that similar neurochemical mechanisms regulate medial amygdaloid modulation of both forms of hypothalamically elicited aggression. The final aspect of this study utilized the combination of retrograde-tracing of amygdaloid neurons into the medial hypothalamus after microinjections of Fluoro-Gold into defensive rage sites, and the immunocytochemical analysis of substance P neurons within the amygdala. The data indicated that large numbers of retrogradely and immunocytochemically positive labeled cells were identified in the medial nucleus, including many that were double-labeled.(ABSTRACT TRUNCATED AT 400 WORDS)

The Neurobiological Bases for Development of Pharmacological Treatments of Aggressive Disorders

Violence and aggression are major causes of death and injury, thus constituting primary public health problems throughout much of the world costing billions of dollars to society. The present review relates our understanding of the neurobiology of aggression and rage to pharmacological treatment strategies that have been utilized and those which may be applied in the future. Knowledge of the neural mechanisms governing aggression and rage is derived from studies in cat and rodents. The primary brain structures involved in the expression of rage behavior include the hypothalamus and midbrain periaqueductal gray. Limbic structures, which include amygdala, hippocampal formation, septal area, prefrontal cortex and anterior cingulate gyrus serve important modulating functions. Excitatory neurotransmitters that potentiate rage behavior include excitatory amino acids, substance P, catecholamines, cholecystokinin, vasopressin, and serotonin that act through 5-HT(2) receptors. Inhibitory neurotransmitters include GABA, enkephalins, and serotonin that act through 5-HT(1) receptors. Recent studies have demonstrated that brain cytokines, including IL-1beta and IL-2, powerfully modulate rage behavior. IL-1-beta exerts its actions by acting through 5-HT(2) receptors, while IL-2 acts through GABAA or NK(1) receptors. Pharmacological treatment strategies utilized for control of violent behavior have met with varying degrees of success. The most common approach has been to apply serotonergic compounds. Others included the application of antipsychotic, GABAergic (anti-epileptic) and dopaminergic drugs. Present and futures studies on the neurobiology of aggression may provide the basis for new and novel treatment strategies for the control of aggression and violence as well as the continuation of existing pharmacological approaches.

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.

Subicular projections to the posterior cingulate cortex in rats.

Abstract The subicular cortex and not Ammons horn has been previously shown to receive afferents from the posterior cingulate cortex. Utilizing the techniques of horseradish peroxidase histochemistry and amino acid autoradiography we present evidence that in the rat the dorsal subicular cortex has a reciprocal connection with the posterior cingulate cortex. The prosubiculum has a small projection to the ventral portion of the retrosplenialis granularis. The presubiculum has the most massive projection to layers III (IV) of the retrosplenial is granularis which extends dorsally up to the border of the retrosplenialis agranularis. Relations of the presubicular component of the hippocampal formation with other components of the Papez circuit are discussed.

The pathways mediating affective defense and quiet biting attack behavior from the midbrain central gray of the cat: an autoradiographic study.

The purpose of this study was to describe the pathways which mediate feline affective defense and quiet biting attack behavior elicited from the midbrain central gray. In these experiments, methods of [3H]leucine and 2-deoxy-[14C]glucose (2-DG) radioautography were utilized in concert with the technique of electrical and chemical brain stimulation. Affective defense behavior elicited from the midbrain central gray is characterized by marked vocalization such as hissing and growling, pupillary dilatation, urination and piloerection. In contrast, quiet biting attack elicited from the midbrain central gray lacks overt autonomic signs observed with affective defense response as well as the stalking component which is typically associated with stimulation of the lateral hypothalamus. Nevertheless, central gray-elicited attack resulted in a directed bite of the neck of an anesthetized rat in a manner similar to that observed from the hypothalamus. Affective defense was elicited from the dorsal half of the midbrain central gray, while quiet biting attack was obtained following stimulation of the ventral half of the midbrain central gray, thus indicating a functional differentiation of the central gray with respect to these two forms of aggression. In a separate series of experiments, affective defense or quiet biting attack response was identified by electrical stimulation through a cannula electrode situated in the midbrain central gray. The affective defense responses were subsequently elicited following microinjections of D,L-homocysteic acid through the same cannula electrode in order to demonstrate that these responses were the result of direct stimulation of cell bodies within the central gray. Then, one of the following autoradiographic tracing procedures was utilized: (1) [3H]leucine was injected through a cannula electrode and the animal was sacrificed after a 4- to 14-day survival period; or (2) a 2-DG solution was systemically injected and electrical stimulation was applied through the cannula electrode in order to metabolically activate the pathways associated with each of these responses. In general, the pattern of labelled target regions as indicated by 3H-amino acid radioautography was similar to that obtained from the 2-DG autoradiographic analysis. The principal ascending pathway associated with affective defense was traced to the anteromedial hypothalamus and medial thalamus. Concerning descending projections, label was traced into the central tegmental fields of the midbrain and pons, locus coeruleus and motor and main sensory nuclei of the trigeminal complex.(ABSTRACT TRUNCATED AT 400 WORDS)