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ROLE OF THE MESOLIMBIC CHOLINERGIC PATHWAYS IN THE INITIATION OF VOCALIZATION IN CATS AND RATS
Stefan M. Brudzynski
Department of Psychology, Brock University
St. Catharines, Ontario, L2S 3A1 Canada
The vocal component of defensive behaviour, with other accompanying manifestations, may be reproduced by an electrical or chemical stimulation of the brain. Results of studies during the last 10 years have demonstrated that the defensive or alarm vocalizations may be induced by cholinergic, muscarinic stimulation of the homolog areas of cat and rat brains. These cholinoceptive muscarinic regions occupy in both these species an elongated medial strip of tissue from the brainstem periaqueductal grey, medial tegmental regions, medial hypothalamic-preoptic and periventricular regions, up to the mediobasal forebrain and septal structures. The following presentation summarizes results of several recent studies which demonstrate that the ascending mesolimbic cholinergic projection from the laterodorsal tegmental nucleus is responsible for triggering the ultrasonic alarm calls (22 kHz calls) in adult rats. It is suggested that this mesolimbic cholinergic projection plays a similar role in the cat's brain. Release of acetylcholine from the mesolimbic cholinergic terminals distributed predominantly along the medial limbic structures, causes a dose dependent postsynaptic inhibition of neuronal firing. It is postulated that this vast inhibitory response represents a trigger for the behavioural response and alarm or threatening vocalization.
Vocalization accompanying defensive behaviour is produced in a species-specific way, depending on the biology of the species, its social structure and behavioural situation. For instance, vocalization may be emitted as a threatening call, like growling vocalization in the cat, which is usually addressed to a single opponent, or as a ultrasonic alarm call, like 22 kHz calls emitted by rats and usually addressed to many individuals in the colony. Despite of these differences, however, it seems that the defensive calls are controlled by a common neural and neurochemical substrate and may be reproduced by electrical or chemical stimulation of the brain. Defensive or alarm vocalizations can be induced by muscarinic cholinergic stimulation of the homolog areas of the cat and rat brains.
RESULTS AND DISCUSSION
Species-specific growling type of vocalization have been induced in cats by intracerebral carbachol from an elongated, but limited strip of medial structures, from the periaqueductal gray, through the medial hypothalamic and preoptic regions, to the septal nuclei, and intralaminar thalamic nuclei (Baxter 1967, 1968; Brudzynski & Eckersdorf 1988; Brudzynski et al. 1995; Decsi 1974; Decsi & Nagy 1977; Myers 1964; Varszegi & Decsi 1967). A diagram of this system compiled from several studies is illustrated on a midsagittal section of the cat brain in Fig.1.
Fig. 1. Midsagittal section through the cat brain with the cholinoceptive strip of medial structures (hatched area) from which the local application of carbachol induced behavioural response with the growling type vocalization as its main manifestation. The strip includes periaqueductal gray, medial tegmentum, medial midbrain reticular formation, zona incerta, posterior and doral hypothalamic regions, perifornical hypothalamic region, para- and pariventricular hypothalamic nuclei, anterior hypothalamic-preoptic area, nucleus of the diagonal band, nucleus of commissure anterior, septal nuclei, and intralaminar thalamic nuclei. The diagram has been compiled from data obtained from Baxter 1967, Brudzynski et al. 1995, Decsi 1974, and Decsi & Nagy 1977. The cholinergic innervation originates from the LDT nucleus (cross hatched area). Abbreviations: CA - commissura anterior, CH - optic chiasm, CO - colliculi, HY - hypothalamus, LDT - laterodorsal tegmental nucleus, MM - mammillary bodies, SE - septum, TH - thalamus, TE - tegmentum.
Intracerebral application of carbachol into the rat brain was also reported to induce vocalization, which was indistinguishable from the naturally occurring 22 kHz ultrasonic alarm calls (Brudzynski & Bihari 1990). Functional mapping of the response induced by carbachol from the rat brain delineated a similar brain system to that one in the cat brain (Brudzynski 1994; Dencev et al. 1996). A similar strip of medially located regions from the tegmentum to the preoptic area and septum has been revealed. A diagram of this cholinoceptive strip of structures is shown on a midsagittal section of the rat brain in Fig. 2.
Fig. 2. Midsagittal section through the rat brain with the cholinoceptice strip of medial structures (hatched area) from which the local application of crabachol induced behavioural response with the 22 kHz type of alarm calls as its main manifestation. The strip includes rostral reticular formation, prerubral field, zona incerta, dorsal hypothalamus, para- and pariventricular hypothalamic nuclei, medial hypothalamic area, anterior hypothalamic-preoptic area, diagonal band of Broca, medial-ventral pallidum, anteromedial nucleus accumbens, and septum. The diagram has been compiled from data obtained from Brudzynski 1994, Dencev et al. 1996, and Dencev & Brudzynski - unpublished observations). The cholinergic innervation originates from the laterodorsal tegmental nucleus (LDT) (cross hatched area). Abbreviations: see legend to Fig. 1.
The patterns of cholinoceptice structues shown in Fig. 1 and 2 are strikingly similar to the pattern of the ascending projections from the pontomesencephalic cholinergic neurons (Satoh & Fibiger 1986; Woolf et al. 1990). This group of cholinergic neurons is localized within the pedunculopontine, parabrachial, and latrodorsal tegmental nuclei (LDT) (Armstrong et al. 1983; Kimura et al. 1981; Lauterborn et al. 1993; Mesulam et al. 1989). The ascending component of the cholinergic innervation, however, originates predominantly from the LDT nucleus.
It has been shown in a behavioural-pharmacological study in rats that chemical stimulation of the LDT nucleus with glutamate induced 22 kHz alarm calls which were similar to those obtained by carbachol from the basal forebrain regions (Brudzynski & Barnabi 1996). Glutamate has a strong, non-specific excitatory effect on neuronal cell bodies and its application into the LDT activated cholinergic neurons within this nucleus. The LDT neurons have extensive ascending projections and innervate numerous nuclei in the thalamus, hypothalamus, basal forebrain, septum, and basal ganglia (Cornwall et al. 1990; Satoh & Figiber 1986). Activiation of these cholinergic cells was reported to release acetylcholine in the basal forebrain (Consolo et al. 1990). Thus, stimulation of these cholinergic cells with glutamate caused release of acetylcholine in most of the nuclei of the cholinoceptive vocalization system and triggered ultrasonic alarm vocalization (Brudzynski & Barnabi 1996).
In order to demonstrate that this mechanism is responsible for the initiation of vocalization, the 22 kHz calls have been induced by an intra-LDT injection of glutamate and this response was antagonized by the local application of scopolamine, a muscarinic antaginist, into the hypothalamic-preoptic area. The medial hypothalamic-preoptic area is a significant portion of the terminal field of the cholinoceptive vocalization strip and receives cholinergic innervation from the LDT nucleus (Satoh & Fibiger 1986). The pretreatment of the anterior hypothalamic-preoptic area with scopolamine significantly decreased the number of ultrasonic calls and the total duration of the response induced by glutamate from the LDT (Fig. 3).
Fig. 3. Average number of 22 kHz alarm calls (left three bars) and average duration of the vocal response (right three bars) induced by injection of glutamate into the laterodorsal tegmental nucleus (LDT) with different pretreatments. Blank bars: response after injection of L-glutamate (GLU) without preteratment; Hatched bars: L-glutamate-induced response after bilateral preteratment of the anterior hypothalamic-preoptic area with saline (2 x 0.2 m l, SAL + GLU); Black bars: L-glutamate-induced response after bilateral pretreatment of the anterior hypothalamic-preoptic area with (-)-scopolamine (2 x 2 m g in 2 x 0.2 m l, SCO + GLU). Vertical lines represent SEMs. Number of calls and response duration after pretreatment with scopolamine were significantly attenuated as compared with those after saline pretreatment (Wilcoxon signed rank test: * - P < 0.02, and ** - P < 0.006). From Brudzynski & Barnabi 1996).
A similar result has been recently replicated with the scopolamine pretreatment of the septum (Dencev & Brudzynski, unpublished data).
The cellular mechanism by which the ascending cholinergic inputs initiate vocalizational responses is not clear. However, it has been found in acute rat preparation that carbachol caused a decrease in the firing rate of spontaneously active neurons in the anterior hypothalamic-preoptic area (Brudzynski et al. 1991; 1998). The deacrease in the firing rate was obtained from a comparable regions to those from which vocalizational responses had been induced. In a recent study, the decrease in the mean firing rate of neurons in the anteromedial hypothalamic-preoptic area was replicated by an electrical stimulation of LDT - the source of the ascending cholinergic projection (Brudzynski et al. 1998). Single pulse electrical stimulation of the LDT caused current-dependent inhibitition of firing, which could stop generation of action potentials in hypothalamic-preoptic neurons for as long as 50 ms. It was also possbile to demonstrate that tha same neurons which inhibited their firing rate to eletrical stimulation of the LDT showed also a dose-dependednt inhibition of firing caused by the local extracellular inotophoresis of carbachol (Fig. 4).
Fig. 4. Responses of the same single neuron in the naterior hypothalamic-preoptic area to electrical stimulation of the laterodorsal tegmental nucleus (LDT) (A-B) or to local iontophoresis of carbachol (C). A: Peristimulus histogram showing that electrical stimulation (S) of the LDT caused inhibition of the firing rate. B: The inhibition was reversed by local iontophoretic preteratment of the neuron with scopolamine (+SCOP). C: Iontophoretic application of carbachol (CCh) into the vicinity of the same neuron caused a dose-dependent (40-120 nA) decrease in the neuron firing rate as shown on the running time histogram (left side of the histogram). Responses to iontophoretic carbachol (80-120 nA) were reversed or attenuated by a concurrent local application of scopolmine (SCO + CCh, right side of the histogram). The same unit responded with an increase in firing rate to iontophoretic application of glutamate (GLU, 30 nA, far right). For further details of the experiment see the sourse paper, Brudzynski et al. 1998.
It seems, therefore that a widespread neuronal inhibition caused by release of acetylcholine from the the mesolimbic cholinergic projection is associated with the initiation of defensive behaviour with threatening or alarming vocalizations. A number of studies provided evidence for a behaviour-dependent decrease in the firing rate at least within the hypothalamic-preoptic area (Adams 1968; Mink et al. 1983; Naka & Kido 1967). On the basis of our results and previous behavioural studies, it is postulated that the vast inhibitory influence of the ascending choliergic fibres in the mediobasal forebrain and diencephalon represents a trigger for the behavioural response and alarm or threatening vocalization.
The studies have been supported by grants from the Natural Sciences and Engineering Research Council of Canada.
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