The Posterior Perforated Substance: A Brain Mystery Wrapped in an Enigma

The Posterior Perforated Substance: A Brain Mystery Wrapped in an Enigma

 

Abstract:

IMPORTANCE:

There is a dearth of published information on the posterior perforated substance (PPS) as compared to the anterior perforated substance.  We managed to glean facts about the PPS that can serve as a landmark for surgical operations in the adjacent regions of the midbrain and the vessels passing through it. Moreover, PPS contains the interpeduncular nucleus responsible for the mental state of the individual.

OBJECTIVES:

1) To describe the anatomy and topography of the blood vessels supplying the PPS area; 2) to review surgical interventions in patients with aneurysm of cerebral arteries; 3) to investigate the interpeduncular nucleus, its vasculature, and its functions;

DESIGN, SETTING:

We assembled and analyzed results from source databases by Elsevier, NCBI MedLine, Scopus, Scholar.Google and Embase. Each article was studied in detail for practically useful information about the PPS.

MAIN OUTCOMES:

During the surgical treatment of cerebral aneurysms, the PPS area is vulnerable to injuries from disrupting the integrity of the small arterial branches that penetrate the PPS. There is possible collateral damage to the interpeduncular nucleus as well.

RESULTS:

The P1-segment perforating branches of the posterior cerebral artery supply the PPS.  This area is especially vulnerable in the case of vascular pathologies, such as an aneurysm of the upper basilar artery. The posterior communicating artery can block the surgeon’s view and impede maneuverability of the tool in the area of the PPS, which may be addressed using the separation technique, which can lead to positive results. In addition, the medial habenula-interpeduncular nucleus in the PPS is associated with various addictions, psychiatric conditions, mood swings, and impacts on sleep.

CONCLUSIONS AND RELEVANCE:

The PPS area is of great interest for surgical interventions. Future studies of the medial habenula-interpeduncular nucleus way inform the development of drugs to affect different types of dependencies and some mental diseases.

Keywords:

posterior perforated substance; interpeduncular fossa; thalamoperforating arteries; posterior communicating arteries; medial habenula; MHb;  interpeduncular nucleus; IPN; MHb-IPN axis; MHb-IPN way.

Introduction

The anatomical structure of the mesencephalic ventral surface, known as the posterior perforated substance (PPS) has a complex topography. That can lead to problems during surgical interventions in the area. The PPS forms the bottom of the third ventricle. It is infiltrated by small branches of the posterior cerebral arteries that carry blood to the thalamus. In addition, the PPS contains the interpeduncular nucleus (IPN). The IPN has a broad inhibitory effects and is connected to inputs via the medial habenula and outputs to the thalamus, various nuclei, and the hypothalamus.  Knowledge of the topography, histology, and vascularization enable the surgeon to use the PPS as a landmark during surgical interventions on adjacent areas of the mesencephalon and vessels passing through it.

In open sources, there is a lack of information about the PPS compared to the anterior perforated substance.  This study addresses the insufficient knowledge. Therefore, this review will be useful both for medical students and for specialists in the field of neurology and neurosurgery.

Objective

The purpose of this article is to provide a detailed review of the PPS using various sources.

Accordingly, the authors sought to:

1) Describe the anatomy and topography of the blood vessels supplying the PPS;

2) Review surgical interventions in patients with aneurysm of the upper part of the basilar artery; and

3) Investigate the IPN as well as its functions.

Materials and methods

The published literature was analyzed relative to the PPS, its arterial supply, surgical operations, as and neural pathways. Sources included databases by Elsevier, NCBI MedLine, Scopus, Scholar. Google, and Embase.  We restricted the search to January 1900 through April 2019.

Interpeduncular fossa and the PPS

There is a depression on the ventral side between right and left peduncles of the midbrain. This depression is known as the interpeduncular fossa and Tarin’s fossa (Figure 1A). It is narrow at the upper margin of the pons, expands anteriorly and ends just near two mammillary bodies identified as the diencephalon.  Tarin’s fossa is delimited:

• Cranially, by the mammillary bodies (4 to 6 mm in diameter) and the anterior half of the posterior perforated substance;
• Dorsally, by the posterior half of the PPS and the anterior part of the mesencephalic tegmentum;
• Caudally, by the superior area of the pons, which extends beyond the interpeduncular fossa in the anterior direction, and the mesencephalopontine sulcus;
• Laterally, by the prolapsing cerebral peduncles, their salient ventral part anterior to the substantia nigra area called “crus cerebri”; and
• Ventrally, by the bifurcation of the basilar artery and the proximal section of both posterior cerebral arteries.

The surface of the interpeduncular fossa has a tint of gray and is penetrated by numerous blood vessels. This formation of the mesencephalon is called the posterior perforated substance or paramedian perforated substance (Figure 1B). The PPS is a triangular depression that consists of gray matter formed by a cluster of neural cell bodies that forms the bottom of the third ventricle.

The base of this plate is triangular with length of 3.25 ± 0.29 mm. It is located anteriorly, in front of the posterior margin of the mammillary bodies. The top part of the plate is located posteriorly and is formed by the diverging angle of the cerebral peduncles and the mesencephalopontine sulcus. The distance between the top of the plate and its base is 8.11 ± 1.19 mm. All in all, the PPS has 4 parts: anterior, posterior, top, and low.

Blood supply of the PPS area

The arteries supplying the diencephalon penetrate the top part, the arteries supplying the mesencephalon penetrate the low and posterior parts

^1,2

.  The posterior communicating artery originates from the posterior-medial surface of the internal carotid artery, passes behind (in the upper-medial direction) the oculomotor nerve, and joins the posterior cerebral artery

³

. For clarity, the posterior cerebral artery is divided into four segments which are designated as P1, P2, P3 and P4

^3,4,5,6

.

The P1 segment is called the pre-connective segment. It originates from the bifurcation of the basilar artery, bends the oculomotor nerve from above (in relation to the anterior-medial part of the cerebral peduncle), and connects with the posterior communicating artery. The P1 segment is usually the origin of such important branches as the thalamoperforating arteries, the short circumflex arteries, the long circumflex arteries, and sometimes the medial posterior choroidal arteries

³

. They supply crucial structures: the interpeduncular fossa, posterior perforated substance, cerebral peduncles, the mamillary bodies, tegmentum, thalamus, hypothalamus, internal capsule and the deep nuclei of the basal ganglia, brainstem and quadrigeminal plate

^7,8,9

. Therefore, damage to any of these branches leads to serious consequences.

Perforating branches of the P1 segment are vulnerable to injury during surgery on vascular pathologies such as basilar apex aneurysms. This type of pathology remains the most common of posterior circulation aneurysms and remains difficult to treat with surgical methods. During the surgery it is extremely important to identify and preserve these perforators. Thus, comprehensive knowledge about the microsurgical anatomy of this area is necessary to prevent undesirable postoperative consequences

¹⁰

.

All thalamoperforating arteries originate from the posterior-upper side of the P1 segment. Kaya et al. confirms that in their study thalamopoerforating artery was the most proximal branch among all perforators

¹⁰

.  Rhoton concludes that the branches of the P1 segment refer to the thalamoperforating arteries, the short circumflex arteries, the long circumflex arteries, and to the medial posterior choroidal arteries

³

.  Usually they take off from the superior and posterior sides of the P1 segment with an average value of 4 branches per this segment. P1’s diameter can reach 1.5 mm.

³

These branches mainly pass through the interpeduncular fossa, the posterior perforated substance, the peduncles of the brain, the mammillary bodies, and the posterior part of the mesencephalon.

The largest branch of the P1 segment is the posterior thalamoperforating artery or the medial posterior choroidal arteries, more rarely, the branch that gives rise to both arteries. In most cases, the posterior thalamoperforating arteries pass into the brain through the posterior perforated substance, the medial part of the brain peduncles, and the upper part of the interpeduncular fossa.

The circumflex branches can originate from the P1 and P2 segments. They split into the short circumflex arteries and the long circumflex arteries

³

. The short circumflex arteries medially pass to the long circumflex arteries and to the medial posterior choroidal arteries and reach the medial geniculate bodies

³

. They can supply the cerebral peduncles, the interpeduncular fossa, and the posterior perforated substance. These structures are supplied by thalamoperforating arteries.

The posterior communicating artery gives rise to 2 to 17 perforating branches

^3,9,11,12,13

, which can be divided into tuberoinfundibular, optical, mammillary, and peduncle branches. The posterior communicating artery also gives rise to the pre-mammillary or tuberothalamic artery

¹⁴

.

These perforating branches pass through the posterior perforated substance in the perimamillary or retrooptical region

^9,15

. In 54% of the samples studied by Saeki et al., most of the perforating branches originated from the anterior half of the posterior communicating artery. In 25% of the samples they took off from the posterior half of the posterior communicating artery. In 21% of the samples they equally branched off from both segments

¹²

. The quantity and the size of these perforating branches were not correlated with the diameter of the posterior communicating artery

¹³

.

The anterior choroidal artery mainly branches off the lower lateral posterior wall of the internal carotid artery, which is about 2-4 mm more distal from the posterior communicating artery. The quantity of the perforating branches taking off between the origin of the anterior choroidal artery and the posterior communicating artery varies from 0 to 4. Perforating branches mainly supply the medial temporal structures (the lateral branches are associated with them), the optic tract (associated with the medial branches) and the posterior perforated substance (associated with the upper branches). In most of the hemispheres studied by Michael George Z. et al, the anterior choroidal artery is the only branch of the internal carotid artery

¹⁶

.

M. Yashar S. Kalani et al “The interpeduncular fossa approach for resection of ventromedial midbrain lesions”, 2017

Figure 1A: The interpeduncular fossa is a wedge-shaped depression between the cerebral peduncles. Its bottom is lined with the posterior perforated substance. The most caudal point of the fossa is the superior foramen cecum (it is a depression located in the middle). The oculomotor nerves (the 3rd pair of cranial nerves) extend from the side walls of the fossa.

Figure 1B: Sagittal section of the brain. The following structures are nearby to the posterior perforated substance: the mammillary body, the interpeduncular fossa with the posterior perforated substance in it, the peduncles of the brain, the oculomotor nerves.

https://www.studyblue.com/notes/note/n/pth-508-study-guide-2013-14-stowell/deck/10739381

 

Access to the PPS area during surgery

The posterior communicating artery may obstruct the view and impair instrumental maneuverability during surgical intervention on the interpedicular fossa when the traditional pterional approach technique is realized. The traditional pterional approach for the surgical treatment of cerebral aneurysms was proposed by G. Yasargil. The technique performs an arcuate skin incision from the tragus to the midline along the border of the scalp and subsequent wide incision of the temporal muscle and craniotomy of the frontotemporal region

^9,17

. To increase the working area, the posterior communicating artery can be separated (when it is hypoplastic) (Fig. 2). This innovation was presented by G. Yasargil based on 7 patients with aneurysm of the upper part of the basilar artery

^9,18

. Subsequently, the division of the posterior communicating artery during surgical interventions was performed by other surgeons

^19,20,21

.

This method has been criticized because surgeons are concerned about the disturbance of blood flow in the perforating branches of the posterior communicating artery or the posterior cerebral artery. In addition, there is the risk of ischemia

^22,23,24

. However, in the article “Dividing the posterior communicating fossa: technical aspects and safety” by Niklaus Krayenbühl, M.D., Ali F. Krisht, M.D., F.A.C.S. it was presented a review on a dividing of the posterior communicating artery demonstrated the safety of this procedure if it is carried out on the basis of the recommendations mentioned in the article by Niklaus Krayenbühl et al “Dividing the posterior communicating fossa: technical aspects and safety”, 2007.

Figure 2: Three options for dividing the PComA include cutting close to the P1–P2 junction (top for 88% of patients); dividing it in its middle segment (middle for 8% of patients), and cutting close to its branch from the internal carotid artery (bottom for 4% of patients).

Key: BA – basilar artery; ICA – internal carotid artery.

Interpeduncular nucleus

The interpeduncular nucleus (IPN) is situated in the PPS. The nucleus of the medial habenula (MHb) and the IPN form the dorsal conductive system of diencephalon that transmits signals from the limbic system to the diencephalon and hindbrain

²⁷

. This pathway plays an important role in higher vertebrates in control of the activity of the mesencephalon and the reward mechanism

²⁸

.

The nucleus of the MHb receives afferent signals from a variety of structures including the triangular septal nucleus, septofimbral nucleus, ventral tegmental area, and raphe nuclei

^29,30,31

, nucleus accumbens

²⁸

, locus coeruleus and superior cervical ganglion

³²

, diagonal band nucleus and medial septum

³³

, as well as the median raphe nucleus

^28.34

. According to multiple studies, the MHb may project to the pineal body and may send sparse efferents to the ventral tegmental area

^35.36

.


Nerve fibers also are directed from the IPN to the dorsal and medial suture nuclei

^37,38

, as well as to the lateral habenula

^39,40

. The main innervating source of the IPN is the nucleus of the medial habenula, with afferents arriving from the horizontal limbs of the diagonal band nucleus

⁴¹

, substantia innominata

⁴²

, infralimbic region of the medial prefrontal cortex

⁴³

, preoptic nucleus

⁴⁴

, hypothalamic nuclei

^41,45

, supra-mammillary nucleus

^41,45

, raphe nuclei

²⁸

, nucleus incertus

⁴⁵

, and dorsal tegmental nucleus

⁴⁵

. All these projections are illustrated in the following figure 3:

Ian McLaughlin et al “The MHb and the IPN circuitry is critical in addiction, anxiety, and mood regulation”, 2017.

Designations: Red lines are the projection of the afferent signals, green lines are the projections of the efferent signals.

1-Interleukin-18.

2- Septofimbrial nucleus.

3-Triangular septum.

4-Medial habenula.

5-Hippocampus.

6-Lateral habenula.

7-Pineal body.

8-Dorsal tegmentum.

9-Nucleus incertus.

10-Dorsal nucleus of the seam.

11-Medial nucleus of the seam.

12-Locus coeruleus.

13-Interpeduncular nucleus.

14-Ventral tegmental area.

15-Hypothalamic nuclei.

16-Preoptic area.

17-Nucleus of the diagonal strip.

18-Substantia innominate.

19-Nucleus basalis of Meynert.

20-Bed nucleus of the anterior commissure.

21-Medial septum.

22-nucleus Accumbens.

The IPN and the MHb synthesize and release a large number of neurotransmitters. Numerous studies have found that acetylcholine

⁴⁶

, substance P

^47,48,49

, glutamate and GABA

³³

, norepinephrine

³²

, serotonin

^50,53

and many neuropeptides

^54,55

participate in the transmission of the signal by the dorsal conductive system of the diencephalon. In addition, this circuit has been shown to be involved in the mechanisms that mediate acute and aversive features of withdrawal from multiple drugs, including alcohol, opiates, nicotine, and other stimulants.

The MHb plays an important role in the development of depression

⁵⁶

, in regulating the transmission of monoamine

⁵⁷

, in various processes that suppress depression, control the sleep-wake cycle

⁵⁸

, provide the reward mechanisms

²⁸

, analgesia

^59,60

and behavioral inhibition

⁶¹

. According to the investigated data of the last 40 years, this nucleus affects marital behavior, hormonal response to stress, and nutritional behaviour

^62,28

.  J. S. Morris et al.

⁶³

found a relationship between the activity of the habenula and the degree of depression.  Habenula removal completely blocks the development of helplessness

⁶⁴

, raising the possibility that the habenula could be an effective therapeutic target in treatment-resistant depression.

The IPN, which gathers signals from the medial nucleus of the habenula

⁴¹

, also takes part in the development of helplessness when it becomes activated. Moreover, the IPN receives more acetylcholine than any other region in the mammalian brain

⁶⁵

.  This is interesting given evidence implicating excessive cholinergic tone in the etiology of depression

^{66,67,68,69,70,71}

. Besides, increasing the duration of REM (rapid eye movement) sleep is a marker of endogenous depression

⁷²

. The genesis of this phenomenon is that cholinergic agonists increase the drive for REM sleep

⁷³

. Meanwhile lowering the activity of the interpeduncular nucleus reduces the duration of REM by 79%, without affecting other types of sleep

⁵⁸

.

Thus, the forebrain controls the reward mechanism and the activity of the mesencephalon via connections between the IPN and the MHb

²⁸

. The dorsal diencephalic conduction system plays an important role in the development of depression

⁵⁶

, in regulation of the monoamine transmission

⁵⁷

, also it is involved in various processes that suppress depression, control the sleep-wake cycle and reward mechanisms

²⁸

, analgesia

^59,60

and behavioral inhibition

⁶¹

.

Conclusion

The posterior perforated substance is a triangular depression in the region of the mesencephalon. It consists of a gray matter and forms the bottom of the third ventricle. This area is of great interest for surgical interventions in patients with aneurysm of the upper part of the basilar artery. During surgical manipulation it is recommended that the posterior communicating artery be divided, which has been shown to be safe under certain conditions. The IPN is a special structure in the PPS that is involved in the “the medial nucleus of the habenula-IPN.”  This review has described its neurophysiology, as well as correlation with various pathological dependencies, psychiatric conditions, mood, and impact on sleep. Future studies on the “medial habenula-interpeduncular nucleus” way may be useful for the development of drugs that affect this pathway to address various types of addictions and some mental diseases.

References

1. G. Brassier, X. Morandi, D. Fournier, S. Velut, P. Mercier Origin of the Perforating Arteries of the Interpeduncular Fossa in Relation to the Termination of the Basilar Artery. Interventional Neuroradiology 4: 109-120, 1998;
2. Rhoton AL Jr: Cerebellum and fourth ventricle. Neurosurgery 47 (3 Suppl):S7–S27, 2000;
3. Rhoton AL Jr: The supratentorial arteries. Neurosurgery 51 [Suppl]:S53–S120, 2002;
4. Krayenbuhl HA, Yasargil MG. Cerebral angiography. 2nd ed. Philadelphia, PA: JB Lippincott; 1968. p. 20–84;
5. Zeal AA, Rhoton Jr AL. Microsurgical anatomy of the posterior cerebral artery. J. Neurosurgery 1978; 48:534–59;
6. Saeki N, Rhoton Jr AL. Microsurgical anatomy of the upper basilar artery and the posterior circle of Willis. J Neurosurg 1977; 46: 563–78;
7. Krayenbuhl HA, Yasargil MG. Cerebral angiography. 2nd ed. Philadelphia, PA: JB Lippincott; 1968. p. 20–84;
8. Lazorthes G, Gouhze A, Salamon G. Vaseularization et Circulation Cerebrales. Masson, Paris 1976;
9. Yasargil MG. Microneurosurgery, vol. I. New York, NY: George Thieme Verlag; 1984. p. 5–168;
10. Ahmet Hilmi Kaya, Adnan Dagcinar, Mustafa Onur Ulu, Arif Topal, Yasar Bayri, Aykan Ulus, Cem Kopuz, Bulent Sam. Journal of Clinical Neuroscience. The perforating branches of the P1 segment of the posterior cerebral artery. 17 (2010) 80–84;
11. Gabrovsky A: Microanatomical bases for intraoperative division of the posterior communicating artery. Acta Neurochir (Wien) 144:1205–1211, 2002;
12. Saeki N, Rhoton AL Jr: Microsurgical anatomy of the upper basilar artery and the posterior circle of Willis. J Neurosurg 46:563–578, 1977;
13. Vincentelli F., Caruso G., Grisoli F., Rabehanta P., Andriamamonjy C., Gouaze A.: Microsurgical anatomy of the cisternal course of the perforating branches of the posterior communicating artery. Neurosurgery 26:824–831, 1990;
14. Marinkovic S, Gibo H, Brigante L, Milisavljevic M, Donzelli R: Arteries of the Brain and Spinal Cord: Anatomic Features and Clinical Significance. Alvellino, De Angelis, 1997;
15. Pedroza A., Dujovny M., Cabezudo-Artero J., Umansky F., Berman S.K., Diaz F.G., Ausman J.I., Mirchandani G.: Microanatomy of the premammillary artery. Acta Neurochir (Wien) 86:50–55, 1987;
16. Michael George Zaki Ghali, Visish M. Srinivasan, Kathryn M. Wagner, Sandi Lam, Jeremiah N. Johnson, and Peter Kan. J Cerebrovasc Endovasc Neurosurg. Anterior Choroidal Artery Aneurysms: Influence of Regional Microsurgical Anatomy on Safety of Endovascular Treatment 2018 Mar; 20(1): 47–52;
17. Yasargil MG, Fox JL. The microsurgical approach to intracranial aneurysms. Surg Neurol. 1975; 3:7-14. PMID: 1111150;
18. Yasargil MG, Antic J, Laciga R, Jain KK, Hodosh RM, Smith RD: Microsurgical pterional approach to aneurysms of the basilar bifurcation. Surg Neurol 6:83–91, 1976;
19. Inao S, Kuchiwaki H, Hirai N, Gonda T, Furuse M: Posterior communicating artery section during surgery for basilar tip aneurysm. Acta Neurochir (Wien) 138:853–861, 1996;
20. Tanaka Y, Kobayashi S, Sugita K, Gibo H, Kyoshima K, Nagasaki T: Characteristics of pterional routes to basilar bifurcation aneurysm. Neurosurgery 36:533–540, 1995;
21. Yonekawa Y, Khan N, Imhof HG, Roth P: Basilar bifurcation aneurysms. Lessons learnt from 40 consecutive cases. Acta Neurochir Suppl 94:39–44, 2005;
22. Regli L, de Tribolet N: Tuberothalamic infarct after division of a hypoplastic posterior communicating artery for clipping of a basilar tip aneurysm: Case report. Neurosurgery 28:456–459, 1991;
23. Sugita K, Kobayashi S, Shintani A, Mutsuga N: Microneurosurgery for aneurysms of the basilar artery. J Neurosurg 51:615–620, 1979;
24. Krisht AF, Kadri PA: Surgical clipping of complex basilar apex aneurysms: A strategy for successful outcome using the pretemporal transzygomatic transcavernous approach. Neurosurgery 56 [Suppl 2]:261–273, 2005;
25. McLaughlin, I., Dani, J. A., & De Biasi, M. (2017). The medial habenula and interpeduncular nucleus circuitry is critical in addiction, anxiety, and mood regulation. Journal of Neurochemistry, 142, 130–143.doi:10.1111/jnc.14008;
26. Shumake, J., & Gonzalez-Lima, F. (2003). Brain Systems Underlying Susceptibility to Helplessness and Depression. Behavioral and Cognitive Neuroscience Reviews, 2(3), 198–221.doi:10.1177/1534582303259057 ;
27. Bianco, I. H. and Wilson, S. W. (2009) The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain. Philos. Trans. R. Soc. Lond. B Biol. Sci. 364, 1005– 1020;
28. Sutherland, R. J. (1982) The dorsal diencephalic conduction system: a review of the anatomy and functions of the habenular complex. Neurosci. Biobehav. Rev. 6, 1– 13;
29. Herkenham, M. and Nauta, W. J. (1979) Efferent connections of the habenular nuclei in the rat. J. Comp. Neurol. 187, 19– 47;
30. Phillipson, O. T. and Pycock, C. J. (1982) Dopamine neurones of the ventral tegmentum project to both medial and lateral habenula. Some implications for habenular function. Exp. Brain Res. 45,89– 94;
31. Lecourtier, L. and Kelly, P. H. (2007) A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition. Neurosci. Biobehav. Rev. 31, 658– 672;
32. Gottesfeld, Z. (1983) Origin and distribution of noradrenergic innervation in the habenula: a neurochemical study. Brain Res. 275, 299– 304;
33. Qin, C. and Luo, M. (2009) Neurochemical phenotypes of the afferent and efferent projections of the mouse medial habenula. Neuroscience 161, 827– 837;
34. Conrad, L. C., Leonard, C. M. and Pfaff, D. W. (1974) Connections of the median and dorsal raphe nuclei in the rat: an autoradiographic and degeneration study. J. Comp. Neurol. 156, 179– 205;
35. Ronnekleiv, O. K. and Moller, M. (1979) Brain‐pineal nervous connections in the rat: an ultrastructure study following habenular lesion. Exp. Brain Res. 37, 551– 562;
36. Guglielmotti, V. and Cristino, L. (2006) The interplay between the pineal complex and the habenular nuclei in lower vertebrates in the context of the evolution of cerebral asymmetry. Brain Res. Bull. 69, 475– 488;
37. Groenewegen, H. J., Ahlenius, S., Haber, S. N., Kowall, N. W. and Nauta, W. J. (1986)Cytoarchitecture, fiber connections, and some histochemical aspects of the interpeduncular nucleus in the rat. J. Comp. Neurol. 249, 65– 102;
38. Behzadi, G., Kalen, P., Parvopassu, F. and Wiklund, L. (1990) Afferents to the median raphe nucleus of the rat: retrograde cholera toxin and wheat germ conjugated horseradish peroxidase tracing, and selective D‐[3H]aspartate labelling of possible excitatory amino acid inputs. Neuroscience 37, 77– 100;
39. Massopust, L. C. and Thompson, R. (1962) A new interpedunculodiencephalic pathway in rats and cats. J. Comp. Neurol. 118, 97– 105;
40. Morley, B. J. (1986) The interpeduncular nucleus. Int. Rev. Neurobiol. 28, 157– 182;
41. Contestabile, A. and Flumerfelt, B. A. (1981) Afferent connections of the interpeduncular nucleus and the topographic organization of the habenulo‐interpeduncular pathway: an HRP study in the rat. J. Comp. Neurol. 196, 253– 270;
42. Vertes, R. P. and Fass, B. (1988) Projections between the interpeduncular nucleus and basal forebrain in the rat as demonstrated by the anterograde and retrograde transport of WGA‐HRP. Exp. Brain Res. 73, 23– 31;
43. Takagishi, M. and Chiba, T. (1991) Efferent projections of the infralimbic (area 25) region of the medial prefrontal cortex in the rat: an anterograde tracer PHA‐L study. Brain Res. 566, 26– 39;
44. Shibata, H. and Suzuki, T. (1984) Efferent projections of the interpeduncular complex in the rat, with special reference to its subnuclei: a retrograde horseradish peroxidase study. Brain Res. 296,345– 349;
45. Hamill, G. S. and Jacobowitz, D. M. (1984) A study of afferent projections to the rat interpeduncular nucleus. Brain Res. Bull. 13, 527– 539;
46. McCormick, D. A. and Prince, D. A. (1987) Acetylcholine causes rapid nicotinic excitation in the medial habenular nucleus of guinea pig, in vitro. J. Neurosci. 7, 742– 752;
47. Burgunder, J. M. and Young, W. S. (1989) Neurokinin B and substance P genes are co‐expressed in a subset of neurons in the rat habenula. Neuropeptides 13, 165– 169;
48. Jackson, K. J., Muldoon, P. P., De Biasi, M. and Damaj, M. I. (2015) New mechanisms and perspectives in nicotine withdrawal. Neuropharmacology 96, 223– 234;
49. De Biasi, M., McLaughlin, I. and Klima, M. L. (2016) Chapter 18 ‐ Nicotine and Neurokinin Signaling A2 ‐ Preedy, Victor R, Neuropathology of Drug Addictions and Substance Misuse, pp. 189– 200. Academic Press, San Diego;
50. Kinsey, A. M., Wainwright, A., Heavens, R., Sirinathsinghji, D. J. and Oliver, K. R. (2001) Distribution of 5‐ht(5A), 5‐ht(5B), 5‐ht(6) and 5‐HT(7) receptor mRNAs in the rat brain. Brain Res. Mol. Brain Res.88, 194– 198;
51. Edwards, F. A., Gibb, A. J. and Colquhoun, D. (1992) ATP receptor‐mediated synaptic currents in the central nervous system. Nature 359, 144– 147;
52. Sperlagh, B., Magloczky, Z., Vizi, E. S. and Freund, T. F. (1998) The triangular septal nucleus as the major source of ATP release in the rat habenula: a combined neurochemical and morphological study. Neuroscience 86, 1195– 1207;
53. Sugama, S., Cho, B. P., Baker, H., Joh, T. H., Lucero, J. and Conti, B. (2002) Neurons of the superior nucleus of the medial habenula and ependymal cells express IL‐18 in rat CNS. Brain Res. 958, 1– 9;
54. Sugama, S., Cho, B. P., Baker, H., Joh, T. H., Lucero, J. and Conti, B. (2002) Neurons of the superior nucleus of the medial habenula and ependymal cells express IL‐18 in rat CNS. Brain Res. 958, 1– 9;
55. McLaughlin, I., Dani, J. A. and De Biasi, M. (2015) Nicotine withdrawal. Curr. Top. Behav. Neurosci.24, 99– 123;
56. Shumake, J., Edwards, E. and Gonzalez‐Lima, F. (2003) Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior. Brain Research 963, 274– 281;
57. Aghajanian , G. K. , and Wang , R. Y. , 1977, Habenular and other midbrain raphe afferents demonstrated by a modified retrograde tracing technique, Brain Research. 122 :229–242;
58. Valjakka, A., Vartiainen, J., Tuomisto, L., Tuomisto, J. T., Olkkonen,H., & Airaksinen, M. M. (1998). The fasciculus retroflexus controls the integrity of REM sleep by supporting the generation of hippocampal theta rhythm and rapid eye movements in rats. Brain Research Bulletin, 47, 171-184;
59. Benabid, A. L., & Jeaugey, L. (1989). Cells of the rat lateral habenula respond to high-threshold somatosensory inputs. Neuroscience Letters, 96, 289-294;
60. Fuchs, P., & Cox, V. C. (1993). Habenula lesions attenuate lateral hypothalamic analgesia in the formalin test. Neuroreport, 4, 121-124;
61. Lee, E. H., & Huang, S. L. (1988). Role of lateral habenula in the regulation of exploratory behavior and its relationship to stress in rats. Behavioural Brain Research, 30, 265-271;
62. Sandyk, R. (1991). Relevance of the habenular complex to neuropsychiatry: A review and hypothesis. International Journal of Neuroscience, 61, 189-219;
63. Morris, J. S., Smith, K. A., Cowen, P. J., Friston, K. J., & Dolan, R. J.(1999). Covariation of activity in habenula and dorsal raphe nuclei following tryptophan depletion. Neuroimage, 10, 163-172;
64. Amat, J., Sparks, P. D., Matus-Am at, P., Griggs, J., Watkins, L. R., &Maier, S. F. (2001). The role of the habenular complex in the elevation of dorsal raphe nucleus serotonin and the changes in the behavioral responses produced by uncontrollable stress. Brain Research, 917, 118-126;
65. Woolf, N. J., & Butcher, L. L. (1985). Cholinergic systems in the rat brain: II. Projections to the interpeduncular nucleus. Brain Research Bulletin, 14, 63-83;
66. Charles, H. C., Lazeyras, F., Krishnan, K. R., Boyko, O. B., Payne, M., &Moore, D. (1994). Brain choline in depression: In vivo detection of potential pharmacodynamic effects of antidepressant therapy using hydrogen localized spectroscopy. Progress in Neuropsychopharmacology and Biological Psychiatry, 18, 1121-1127;
67. Dilsaver, S. C., & Coffman, J. A. (1989). Cholinergic hypothesis ofdepression: A reappraisal. Journal of Clinical Psychopharmacology, 9,173-179;
68. Dube, S. (1993). Cholinergic supersensitivity in affective disorders. InJ. J. Mann & D. J. Kupfer (Eds.), Biology of depressive disorders, Part A: A systems perspective (pp. 51-78). New York: Plenum;
69. Janowsky, D. S., el Yousef, M. K., Davis, J. M., & Sekerke, H. J. (1972). Acholinergic-adrenergic hypothesis of mania and depression. Lancet, 2, 632-635;
70. Janowsky, D. S., Risch, S. C., & Gillin, J. C. (1983). Adrenergiccholinergic balance and the treatment of affective disorders. Progress in Neuropsychopharmacology and Biological Psychiatry, 7, 297-307;
71. Steingard, R. J., Yurgelun-Todd, D. A., Hennen, J., Moore, J. C.,Moore, C. M., Vakili, K., et al. (2000). Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy. Biological Psychiatry, 48, 1053-1061;
72. Riemann, D., Berger, M., & Voderholzer, U. (2001). Sleep and depression—results from psychobiological studies: An overview. Biological Psychology, 57, 67-103;
73. Haun, F., Eckenrode, T. C., & Murray, M. (1992). Habenula andthalamus cell transplants restore normal sleep behaviors disrupted by denervation of the interpeduncular nucleus. Journal of Neuroscience, 12, 3282-3290.