An excitatory amino acid projection from ventromedial hypothalamus to periaqueductal gray in the rat: Autoradiographic and electrophysiological evidence

doi:10.1016/0304-3940(88)90352-7

Neuroscience Letters

Volume 85, Issue 2, 29 February 1988, Pages 205-211

https://doi.org/10.1016/0304-3940(88)90352-7 Get rights and content

Abstract

The projection from ventromedial hypothalamus (VMH) to periaqueductal gray (PAG) has been implicated in various physiological processes in the rat, but the neurotransmitter mediating the excitatory response in PAG has not been identified. This pathway has been studied using a combination of anatomical and electrophysiological techniques. The retrograde labelling by d-[³H]aspartate in VMH, following injections into PAG, was particularly dense, suggesting that an excitatory amino acid may be the transmitter. This postulate is strengthened since VMH-evoked synaptic responses in PAG were reduced by microelectrophoretically administered antagonists of excitatory amino acids. Receptors of the $N- methyl- d -aspartate$ and $non -N- methyl- d -aspartate$ types appear to have a functional role in this projection.

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Activity at NMDA glutamate receptors is relevant because CSF glutamate levels are reported to correlate with measures of aggression so that subjects with high CSF glutamate levels are more aggressive than those with low CSF glutamate levels (Coccaro et al., 2013). If, based on animal studies, activation of NMDA glutamate receptors leads to aggression (Bandler 1984; Beart et al., 1998; Beitz 1989; Duncan et al., 2004; Lu et al., 1992; Schubert et al., 1996; Shaikh et al., 1994), KYNA might act to reduce aggression while QA might act to increase aggression. Finally, while less is known about the physiologic role of PA, this KYN pathway metabolite has been reported to antagonize the neurotoxic, though not the glutaminergic agonist effects of QA (Beninger et al., 1994; Cockhill et al., 1992).
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NUCB1 mRNA and protein was found to be present in all brain regions, extending to the spinal cord and dorsal root ganglia. Double-staining for NUCB1 and NeuN, glial fibrillary acidic protein and myelin basic protein revealed that NUCB1 is exclusively found in neurons, and not in glial or ependymal cells. Notably, NUCB1-immunoreactivity was observed in all neurons examined, making no distinction between previously identified glutamatergic and GABAergic populations, including those that are known not to stain for NeuN. This included the markedly more restricted population of NUCB2-expressing neurons in the brain. The protein was detected in cell somata and proximal dendrites, but not in axons or terminal structures. Further examination of the subcellular distribution of NUCB1 using organelle-specific markers revealed its consistent presence in the Golgi apparatus.
These findings identify NUCB1 as a novel pan-neuronal marker. Along with the recent demonstration of broad expression of the protein in endocrine cells, the present results suggest that NUCB1 may play a role in spatiotemporal calcium handling in signaling cells.
Cerebrospinal fluid glutamate concentration correlates with impulsive aggression in human subjects
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Citation Excerpt :
While little work has been reported on the role of glutamate in human aggressive behavior, preclinical studies suggest that stimulation of central glutamate receptors typically increases aggressive behavior in lower mammals. As demonstrated in a number of preclinical studies in rodents, an excitatory amino acid pathway from the medial hypothalamus (MH) to the periaqueductal gray (PAG) is associated with aggressive behavior (Beart et al., 1998, 1990; Beitz, 1989). In the rat, there is a dense and distinct group of glutamatergic neurons expressing glutamate transporter protein over the entire hypothalamic attack area, with the rostral portion predominantly containing glutamatergic, and the caudal portion having both glutaminergic and, to a lesser degree, GABAergic, neurons (Hrabovszky et al., 2005).
Neurochemical studies have pointed to a modulatory role in human aggression for various central neurotransmitters. Some (e.g., serotonin) appear to play an inhibitory role, while others appear to play a facilitator role. While recent animal studies of glutaminergic activity suggest a facilitator role for central glutamate in the modulation of aggression, no human studies of central glutaminergic indices have yet been reported regarding aggression. Basal lumbar cerebrospinal fluid (CSF) was obtained from 38 physically healthy subjects with DSM-IV Personality Disorder (PD: n = 28) and from Healthy Volunteers (HV: n = 10) and assayed for glutamate, and other neurotransmitters, in CSF and correlated with measures of aggression and impulsivity. CSF Glutamate levels did not differ between the PD and HC subjects but did directly correlate with composite measures of both aggression and impulsivity and a composite measure of impulsive aggression in both groups. These data suggest a positive relationship between CSF Glutamate levels and measures of impulsive aggression in human subjects. Thus, glutamate function may contribute to the complex central neuromodulation of impulsive aggression in human subjects.
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Some research suggests PH stimulation mainly elicits defensive flight. The PH shares extensive interconnections with other areas of the brain that would elicit defensive-flight like response when stimulated, such as the periaqueductal gray, reticular formation, and septal complex (Swanson and Cowan, 1979; Beart et al., 1988; Vertes et al., 1995; Vertes and Crane, 1996; Abrahamson and Moore, 2001; Cavdar et al., 2001a); thus supporting the view that its stimulation would engage the functional circuitry involved in such behavior. It is understandable that if the main effect of PH stimulation is flight, the rats would not engage in skilled behavior.
Recent studies have shown that electrical stimulation of the posterior hypothalamic nucleus (PH) facilitates locomotion in control rats, and rats were made akinetic by dopaminergic blockade via haloperidol or dopamine depletion by the neurotoxin 6-hydroxydopamine. These findings suggest that PH stimulation might be a promising treatment for akinesia associated with dopamine loss in Parkinson's disease. The present study further examined the positive effects of PH stimulation on behavior by characterizing its potential facilitatory effects on tasks that require skilled movements. Rats were trained to reach for food pellets with a forelimb (skilled reaching) or press a bar in an operant conditioning task for food. PH stimulation in undrugged rats not only facilitated locomotion in each of the tasks, but also impaired performance of the skilled movement components of the tasks. Haloperidol reduced locomotion and skilled movement, and PH stimulation only restored locomotion. The results are discussed in relation to the idea that PH stimulation selectively facilitates locomotor behavior and may have limited use in restoring impairments in skilled movements and consummatory behavior that results from dopaminergic depletion.
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Noxious tail-shock elicits vocalization afterdischarges (VADs) from rats that have distinct spectrographic characteristics and are a validated model of the affective response to pain. The ventromedial hypothalamus (VMH) is a core structure underlying the generation of affective behaviors to threats and receives nociceptive inputs. VAD-like vocalizations (vocalizations with the same spectral characteristics of VADs) are elicited by electrical or chemical stimulation of the dorsomedial-VMH. Pharmacological manipulation of GABAA receptors within the dorsomedial VMH altered the threshold for elicitation of VADs induced by this stimulation or by tail-shock, and altered the asymptotic level of fear conditioning supported by VMH stimulation or tail-shock. Partial kindling of the basolateral amygdala produced long-term increases in the amplitude of local field potentials recorded from the dorsomedial-VMH that correlated with long-term increases in VAD amplitude elicited by tail-shock. These findings demonstrate that the dorsomedial-VMH contributes to the processing of pain affect, and that the affective dimension of pain belongs to a broader class of sensory experience that represents threat to the individual.
Interplay between glutamate and serotonin within the dorsal periaqueductal gray modulates anxiety-related behavior of rats exposed to the elevated plus-maze
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Several neurotransmitters, including glutamate and serotonin, modulate defensive behaviors related to anxiety in the rat dorsal periaqueductal gray (PAG). Although both glutamate N-methyl-d-aspartic acid (NMDA) and serotonin type 1-A (5-HT_1A) receptors have been shown to interfere with these subtle responses, such as inhibitory avoidance, a possible interaction between them remains to be examined. To address this issue, the present study investigated whether the activation or the blockage of 5-HT_1A receptors located in the dorsal PAG would interact with NMDA function in animals exposed to the elevated plus-maze task. The effect of the NMDA (25 pmol) was evaluated in rats pretreated with the 5-HT_1A receptor antagonist WAY-100135 (2.0 or 5.0 nmol). In addition, the effect of the NMDA (100 pmol) was evaluated in rats pretreated with the 5-HT_1A receptor agonist 8-OH-DPAT (2.0 or 8.0 nmol). Intra-dorsal PAG injection of NMDA (25 pmol) increased inhibitory avoidance behavior. This anxiogenic-like effect of the NMDA was counteracted by the pretreatment with WAY-100135 (5.0 nmol). Although 100 pmol of NMDA failed to increase inhibitory avoidance in the vehicle-pretreated group, in rats pretreated with 8-OH-DPAT this NMDA dose produced an anxiogenic-like effect. These results suggest that 5-HT_1A and NMDA receptors interact in the dorsal PAG to modulate the anxiety-related behavior.

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An excitatory amino acid projection from ventromedial hypothalamus to periaqueductal gray in the rat: Autoradiographic and electrophysiological evidence

Abstract

Neuroscience

Neuroscience

Brain Res.

Brain Res.

Neuroscience

Brain Res.

Exp. Neurol.

Brain Res.

Reticular formation, central gray and related tegmental nuclei

Identification of hypothalamic and midbrain periacqueductal grey neurones mediating aggressive and defensive behaviour by intracerebral microinjections of excitatory amino acids