Anesthetics and the habenulo-interpeduncular system: selective sparing of metabolic activity

doi:10.1016/0006-8993(81)90927-6

Brain Research

Volume 210, Issues 1–2, 6 April 1981, Pages 461-466

https://doi.org/10.1016/0006-8993(81)90927-6 Get rights and content

Summary

The method of regional localization of brain metabolism by [¹⁴C]deoxyglucose during anesthesia in rats shows that pentobarbital, ether and chloral hydrate reduce deoxyglucose uptake in most neuronal regions, with one common exception: spared or increased metabolism is found in the medial habenula, the interpeduncular nucleus, and the habenulo-interpeduncular tract. Prior destruction of afferent inputs abolishes the selective metabolic sparing in the habenulo-interpeduncular system during chloral hydrate anesthesia.

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Uncontrolled stress correlates with helplessness and subsequent failure to escape unpredictable foot-shocks in wild-type Sprague Dawley rats catalyzing elevated metabolic activity in brain regions sensitive to negative mood regulation (Mirrione et al., 2014). The medial habenula and IPN are exceptionally heightened metabolic sections exploited by stress in awake animals, along with general anesthesia and sleep states (Herkenham, 1981). A decrease in volume in the bilateral MHb and LHb is observed in chronically stressed rats using 3D morphological analysis (Jacinto et al., 2017).
The phasic emotion, fear, and the tonic emotion, anxiety, have been conventionally inspected in clinical frameworks to epitomize memory acquisition, storage, and retrieval. However, inappropriate expression of learned fear in a safe environment and its resistance to suppression is a cardinal feature of various fear-related disorders. A significant body of literature suggests the involvement of extra-amygdala circuitry in fear disorders. Consistent with this view, the present review underlies incentives for the association between the habenula and fear memory. G protein-coupled receptors (GPCRs) are important to understand the molecular mechanisms central to fear learning due to their neuromodulatory role. The efficacy of a pharmacological strategy aimed at exploiting habenular-GPCR desensitization machinery can serve as a therapeutic target combating the pathophysiology of fear disorders. Originating from this milieu, the conserved nature of orphan GPCRs in the brain, with some having the highest expression in the habenula can lead to recent endeavors in understanding its functionality in fear circuitry.
Digital autoradiography for efficient functional imaging without anesthesia in experimental animals: Reversing phencyclidine-induced functional alterations using clozapine
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While the method has since been adapted for use in in vivo and clinical setting with 18F-labeled 2-DG (FDG) and positron emission tomography (PET), ARG still enables higher spatial resolution (Koba et al., 2011; Yang et al., 2016; d’Argy and Sundwall, 2000; Solon, 2015; Schmidt and Smith, 2005; Barthe et al., 2012), cheaper costs (Fine et al., 2014; Upham and Englert, 2003), and longer temporal window for imaging (Solon and Kraus, 2001). Due to ARG imaging being performed using dissected ex vivo samples, it also does not require the use of anesthesia or physical restraint during imaging, both of which are known to strongly alter functional brain activity and connectivity, glucose utilization, and several other neurobiological measures (Ohata et al., 1981; Ori et al., 1986; Herkenham, 1981; Kohtala et al., 2016; Theilmann et al., 2019; Boretius et al., 2013; Hildebrandt et al., 2008; Momosaki et al., 2004; Toyama et al., 2004; Eintrei et al., 1999; Lenz et al., 1998; Paasonen et al., 2018; Antila et al., 2017). Thus, the small animal PET and other small animal imaging methods often have significant confounding factors interfering with research of treatments for central nervous system (CNS) disorders.
Autoradiography (ARG) is a high-resolution imaging method for localization of radiolabeled biomarkers in ex vivo specimen. ARG using 2-deoxy-d-glucose (2-DG) method is used in to study drug actions on brain functional activity, as it provides results comparable to clinically used functional positron-emission tomography (PET). The requirement of slow analog detection methods and emerging advances in small animal PET imaging have, however, reduced the interest in ARG. In contrast to ARG, experimental animals need to be restrained or sedated/anesthetized for PET imaging, which strongly influence functional activity and thus complicate the interpretation of the results. Digital direct particle-counting ARG systems have gained attraction during the last decade to overcome the caveats of conventional ARG methods. Here we demonstrate that the well-established 2-DG imaging method can be adapted into use with contemporary digital detectors. This method readily and rapidly captures the characteristic effects of phencyclidine (5 mg/kg, i.p.), a dissociative agent targeting the NMDAR (N-methyl-d-aspartate receptor), on regional glucose utilization in the adult mouse brain. Pretreatment with antipsychotic drug clozapine (6 mg/kg, i.p.) essentially abolishes these effects of phencyclidine on brain functional activity. Digital ARG produces viable data for the regional analysis of functional activity in a fraction of time required for film development. These results support the use of digital ARG in preclinical drug research, where high throughput and response linearity are preferred and use of sedation/anesthesia has to be avoided.
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However, stress-induced activation of the LHb may not only lead to changes in dopaminergic signaling but also to alterations in the activity of serotonergic neurons located in the dorsal and medial raphe nuclei [161–163]. Under general anesthesia, the amount of habenular activity rises [164–166] which suggests that habenular activity can be modulated during the transition from sleep/low arousal states to awake/high arousal states. In line with this, fluctuations in the spontaneous activity of the Hb are regulated by circadian rhythms [86,167].
The habenula is a brain region that has gained increasing popularity over the recent years due to its role in processing value-related and experience-dependent information with a strong link to depression, addiction, sleep and social interactions. This small diencephalic nucleus is proposed to act as a multimodal hub or a switchboard, where inputs from different brain regions converge. These diverse inputs to the habenula carry information about the sensory world and the animal’s internal state, such as reward expectation or mood. However, it is not clear how these diverse habenular inputs interact with each other and how such interactions contribute to the function of habenular circuits in regulating behavioral responses in various tasks and contexts. In this review, we aim to discuss how information processing in habenular circuits, can contribute to specific behavioral programs that are attributed to the habenula.
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The medial habenula (MHb) is a key bridge between limbic forebrain and midbrain monoaminergic centers. Although its exact behavioral function remains enigmatic, it is implicated in regulating many behaviors such as stress responses and circadian rhythm. Fundamental information such as the neurotransmitters in the afferent and efferent projections of the MHb remains unclear. By combining retrograde tract tracing and genetic labeling of GABAergic neurons in mice, we find that the medial septum (MS) and nucleus of diagonal band (NDB) provide GABA-ergic input to the MHb. By anterograde tracing and immunostaining against a marker of glutamatergic synapses, we find that the projection from the triangular septal nucleus (TS) to the MHb has the capacity to release glutamate. This suggests that in addition to ATP, glutamate is another neurotransmitter for the TS→MHb projection. Finally, by combining anterograde tracing and immunostaining, we find that the MHb neurons projecting to the interpeduncular nucleus (IPN) have the capacity to release glutamate. This suggests that, in addition to acetylcholine and substance P, glutamate is another neurotransmitter used by MHb projection neurons. Our findings reveal the organization of two key neurotransmitters for the MHb afferent and efferent projections, and lay framework for future functional studies of this pathway in the brain.
Increase of rat medial habenular mast cell numbers by systemic administration of cyclophosphamide
2003, Toxicology Letters
Cyclophosphamide administration generates systemic toxicity having immune and nervous consequences. After focusing on nervous consequences by studying neuronal activity, we now consider cyclophosphamide impact on diencephalic mast cells as part of the brain immune system. Diencephalon, the ultimate sensory relay before neocortical processing, is the only brain structure containing mast cells. Single cyclophosphamide administration (100 mg/(kg 1 ml ip)) was performed in naturally behaving rats and diencephalic mast cell numbers were analyzed once all drug effects had developed (4 h postinjection). Significant increases were observed only in the medial habenular nucleus—bilaterally and especially in its caudal portion. Mast cell increase is temporally related to behavioral impairment and evoked neuronal activity in a restricted number of visceral/limbic extrathalamic structures. The medial habenular nucleus belongs to the limbic system involved in processing emotional reactions and regulation of the autonomic nervous system. Its involvement during toxic challenge is highly compatible with its presumed function in the maintenance of vital functions.

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: These data first appeared in abstract form in Neurosci. Abstr., 4 (1978) 222.

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Anesthetics and the habenulo-interpeduncular system: selective sparing of metabolic activity

Summary

Brain Research

Amer. J. Med.

Afferent connections of the habenular nuclei in the rat. A horseradish peroxidase study, with a note on the fiber-of-passage problem

J. comp. Neurol.

Efferent connections of the habenular nuclei in the rat

J. comp. Neurol.

A golgi study on the habenular nucleus of the cat

J. comp. Neurol.