[Handbook of Behavioral Neuroscience] Handbook of Mammalian Vocalization - An Integrative...

Stefan M. Brudzynski (Ed.) DOI: 10.1016/B978-0-12-374593-4.00026-7Handbook of Mammalian Vocalization Copyright 2010 Elsevier B.V. All rights reserved.ISBN 978-0-12-374593-4

265

CHAPTER 7.3

Medial cholinoceptive vocalization strip in the cat and rat brains: initiation of

defensive vocalizations

Stefan M. Brudzynski *

Department of Psychology, Brock University, St. Catharines, Ontario, Canada

Abstract : Pharmacological studies performed on cat and rat brains are reviewed, which have allowed for iden-tification of a widespread cholinoceptive system in the mammalian brain responsible for initiation of defensive vocalizations characteristic of aversive behavioral situations. Intracerebral injections of a predominantly mus-carinic agent, carbachol, induced growling and hissing vocalizations in cats and 22 kHz ultrasonic alarm vocali-zations in rats. Brain systems inducing these calls and their neurochemical organization in both the species show a very high degree of homology. This cholinoceptive substrate for these vocalizations, termed the medial cholino-ceptive vocalization strip, is innervated by the ascending fibers from the brainstem cholinergic neurons located in the laterodorsal tegmental nucleus. This nucleus forms a cholinergic component of the ascending activating reticular system and its functions are discussed.

Keywords : medial cholinoceptive vocalization strip; pharmacological stimulation; reticular activating system; carbachol; acetylcholine; growling vocalization; 22 kHz vocalization; mapping; atropine; cat; rat

I . Introduction

Identification of the medial cholinoceptive vocaliza-tion strip has evolved slowly over nearly 40 years of research, conducted initially on cats and then on rats in a number of laboratories. The main evidence for the existence of a cholinoceptive substrate in the brain responsible for production and control of vocaliza-tion and its underlying emotional processes arose from behavioural – pharmacological studies in the early 1960s. Although chemicals were applied to the organism by different routes in these studies, it was the method of direct intracerebroventricular or intracerebral applica-tion of pharmacological agents into the restricted brain regions that allowed for bypassing the blood – brain bar-rier and that had given impetus to this line of study.

I.A . History of early behavioural – pharmacological studies in cats

Probably the first cholinergically-induced vocalization with concomitant emotional behavior was observed after injection of DFP (diisopropylfluorophosphonate) or large doses of acetylcholine into the lateral ventricle of a cat ( Feldberg and Sherwood, 1954a,b ). In these early studies, chemical agents were usually given sys-temically or intraventricularly in large doses and they affected almost the entire central nervous system, causing a complex behavioral outcome with numerous adverse or toxic side-effects. Thus, the observations were predominantly focused on autonomic manifesta-tions (e.g., emesis) and pathological symptoms (e.g., motor dysfunctions, catatonia and epileptic seizures). Such outcomes created initial difficulty in identifying and localizing brain cholinoceptive regions responsi-ble for vocalization and emotional arousal. * Corresponding author. E-mail: [email protected]

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266 Hypothalamic/Limbic Integrative Function for Vocal/Behavioral Outcome

Early pharmacological studies provided substantial evidence that the cholinergic agents, both muscarinic and nicotinic, have a strong activating pharmacologi-cal effect on the central nervous system when given directly into the brain, i.e., bypassing the blood – brain barrier ( Feldberg and Sherwood, 1954a,b ; MacLean, 1957; Feldberg, 1963 ). Intracerebral injections of the cholinomimetic, pilocarpine, in cats induced a number of manifestations described as rage response with auto-nomic symptoms and growling vocalization ( Borison, 1959 ; Zablocka and Esplin, 1964 ). Similar responses were reported after intraperitoneal or subcutaneous application of tremorine and were termed tremorine-induced rage response ( Baker et al., 1960 ; Funcke et al., 1962 ; Koff and Langfitt, 1966 ). Tremorine is metabolized to oxotremorine, a potent muscarinic agonist ( Cho et al., 1961 ; George et al., 1962 ), which was responsible for initiation of the tremorine-induced rage. Also, intravenous or intraventricular application of such cholinomimetics as oxotremorine, pilocarpine, arecoline, physostigmine (eserine), neostigmine, mus-carine, McN-A-343 and carbachol were able to induce a similar rage response with accompanying manifesta-tions ( Leslie, 1965 ; Andjelkovic et al., 1971 ; Beleslin et al., 1973, 1974 ; Beleslin and Samardžic, 1977, 1979 ). Results of these early studies have also shown that the cholinergically-induced emotional manifesta-tions and vocalization were antagonized by atropine, scopolamine and l-hyoscyamine, indicating muscarinic nature of the response ( Baker et al., 1960 ; Leslie, 1965 ; Koff and Langfitt, 1966 ; V á rszegi and Decsi, 1967 ; Romaniuk et al., 1973a ; Beleslin et al., 1974 ).

Responses to these cholinergic muscarinic drugs were replicated by a direct intracerebral application of acetylcholine with physostigmine, physostigmine itself, or carbachol in a form of intracerebral crystalline microimplants in cats and rabbits ( Nashold and Gills, 1960 ; Hern á ndez-Pe ó n et al., 1963 ). Chemostimulation by microimplants of crystals is disadvantageous from the pharmacological point of view. The crystals dis-solve slowly in the interstitial fluid, creating local solutions of varying and probably locally very high concentrations. The induced symptoms often formed a combination of activation of physiologically oppo-site mechanisms (e.g., emotional activation and sleep atonia), activation of some receptors in a non-specific way at large doses, as well as deactivation of local cir-cuits by an overstimulation effect (for that last effect, see Brudzynski and Eckersdorf, 1988 ). Nevertheless, it was possible to induce emotional responses (rage) in cats, with growling and hissing vocalizations, which

were potentiated by provocation or approach of the experimenter, and that could even lead to a defensive attack. The most significant finding was that the brain presented a regional sensitivity to cholinergic stimula-tion and that cholinosensitive regions were stretched from rostral mesencephalon, through basal dien-cephalon to basal telencephalon ( Nashold and Gills, 1960 ). The chemosensitive structures included the septum, anterior commissural region, preoptic area, medial hypothalamus, perifornical region and many other neighboring structures, as well as the periaque-ductal gray ( Hern á ndez-Pe ó n et al., 1963 ).

The question arose of how critical is the cholino-ceptive region for induction of vocalization and emo-tional state. A series of localized electrolytic lesions placed in the cat limbic system were able to block the systemic tremorine-induced rage response and vocali-zation ( Koff and Langfitt, 1966 ). The most effective lesions were found in many limbic structures including the posterior part of the hypothalamus (mammillary nuclei), septum, anterior fornical area, lateral amyg-dala and posterior hippocampus. It was also noticed that lesions placed in other subcortical and cortical regions did not have such a blocking effect ( Koff and Langfitt, 1966 ). In another study, surgical isolation of the hypothalamus (surgical deafferentation) prevented development of the rage response after systemic oxotremorine ( Gell é n et al., 1972 ). Based on these results, the hypothalamus seemed to be the particular structure, or at least one of the critical structures, for expression of the cholinergically-initiated vocalization and underlying emotional response.

The series of studies that followed dealt with a direct intracerebral cholinergic stimulation of the hypothalamus and other limbic structures (e.g., sep-tum) with carbachol or acetylcholine ( Myers, 1964 ; Endr ö czi et al., 1964 ; Baxter, 1967 ; V á rszegi and Decsi, 1967 ; MacPhail and Miller, 1968 ; Vahing and Allikmets, 1970 ; Romaniuk et al., 1973b ; Allikmets, 1974 ; Decsi, 1974 ). All of these studies consistently reported a drug-induced emotional response, termed “ rage response, ” “ emotional-defensive response, ” or “ emotional-aversive response ” ( Brudzynski, 1981b ; Brudzynski and Eckersdorf, 1988 ) with prolonged growling vocalization and, to a lesser degree, hissing or spitting (a modified form of hiss). The response was accompanied by characteristic somatic and autonomic symptoms, such as back arching, retreat, striking with paws and sometimes attacking (when provoked), sali-vation, piloerection, mydriasis, hyperpnoea, tremor, etc. ( Brudzynski, 1981a ); all known from the studies

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Medial cholinoceptive vocalization strip in the cat and rat brains: initiation of defensive vocalizations 267

with electrical stimulation of the relevant regions of cat hypothalamus and other brainstem structures ( Hunsperger, 1956 ; Hunsperger and Bucher, 1967 ; Brown et al., 1969a,b ; see also Siegel et al., Chapter 7.1 in this volume).

A similar emotional response was obtained by injec-tion of acetylcholine to some other extrahypothalamic structures, such as the medial amygdala (bordering far lateral hypothalamus, Allikmets et al., 1969 ), or by injection of carbachol to the medial nucleus caudatus or ventral thalamic nucleus ( Hull et al., 1967 ), as well as to the septum, intralaminar nuclei of thalamus and the red nucleus ( Decsi, 1974 ; Decsi and Nagy, 1977 ). Carbachol could also induce the emotional-defensive response with growling vocalization from the peri -aqueductal gray matter, ventral tegmentum and the mesencephalic reticular formation ( Baxter, 1968 ; Decsi, 1974 ; Karmos-V á rszegi and Karmos, 1977a,b ). In spite of the fact that the anteromedial hypothala-mus and preoptic region seemed to be the main target for cholinomimetics in inducing the emotional-defen-sive response, there were other regions of the brain producing a similar response. The response, however, was structure-specific, and intracerebral injections of carbachol to the globus pallidus, putamen, dorsal and ventral hippocampus, all amygdaloid nuclei, or white matter were ineffective in inducing vocalizations or autonomic symptoms ( Decsi, 1974 ). Similarly, a microinjection of carbachol close to the locus coeru-leus induced sleep-like atonia and not an emotional response (van Dongen et al., 1978).

A further careful mapping of the brain was needed for the carbachol-induced response and to redefine the cholinoceptive regions associated with induction of vocalization and the emotional response in the cat. It was also important to answer the question “ What behavioral response will be mapped? ” i.e., to clar-ify whether the cholinergically-induced response is defensive (retreat) or offensive (attack) in nature.

I.B . Nature of the carbachol-induced behavioral response in cats

Results of early studies on cats have indicated that the cholinergically-induced emotional response evoked from a number of brain structures was structure-specific and somewhat different for different brain regions, and it might not represent the offensive type of aggression. Frequent attempts of cats to escape from the experimental cage during the muscarine- or

carbachol-induced response led to the conclusion that the cholinergically-induced response with attacks represents a “ fear and irritable kind of aggression ” ( Beleslin and Samardžic, 1977 ).

Hern á ndez-Pe ó n and his colleagues were the first researchers to observe that attacks evoked during the cholinergically-induced rage were dependent on the stimulated structure of the brain ( Hern á ndez-Pe ó n et al., 1963 ). It was later reported that cats, which showed a consistent attack response against mice before injection, retreated from a mouse placed in front of them under the carbachol-induced response; they also ignored milk pre-sented to them ( Baxter, 1967 ; Hull et al., 1967 ). On the other hand, carbachol injected into the ventral tegmen-tum made cats kill mice violently, while this response did not occur from the anterior hypothalamic region, and cats injected with carbachol in the hypothalamic region still retreated from a mouse ( Karmos-V á rszegi and Karmos, 1977a,b ). As a matter of fact, cats injected with carbachol in the anterior hypothalamus were retreating from any other animal or large object placed in the cage in front of them (unpublished observations). Further detailed studies have clarified that, during the carbachol-induced affective state, cats always retreated from the researcher if they were given space to do so, and never attacked. The response was not aggressive but defensive in nature, justifying the term “ emotional-defensive response ” ( Brudzynski, 1981a ). The response was also aversive in nature. An extended hand toward the animal, which represented an “ indifferent ” stimu-lus without any aversive response in the control condi-tions, acquired aversive properties after administration of carbachol. Cats always retreated from the approach-ing human hand, and the magnitude of their growling vocalization was proportional to the distance between the cat and the hand ( Brudzynski et al., 1993b ).

The conclusions about the defensive nature of the cholinergically-induced affective state with growling vocalization were consistent with ethological obser-vations that growling vocalization in cats appears only in defensive situations, e.g., it would be emitted by the defending cat cornered by an aggressive oppo-nent ( Leyhausen, 1979 ).

II . Quantitative mapping studies of cholinergically-induced vocalization in cats

The question arose, “ What features of the choliner-gically induced response should be measured for the brain mapping purpose? ” Results of several studies

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have shown that, although many of the carbachol-induced symptoms were dose-dependent ( V á rszegi and Decsi, 1967 ; Beleslin and Stefanovic-Denic, 1986), the time of growling vocalization, and to a lesser degree the number of growls, were not only dose-dependent but they reflected in the best way the time-course and the dynamics of the pharmacologi-cal response ( Decsi et al., 1969 ; Brudzynski, 1981b ; Brudzynski and Eckersdorf, 1988 ). Time of growling was also a predictive measure of the magnitude of the carbachol-induced response. Cumulated time of growl-ing was inversely proportional to the distance between the cat and the gloved human hand as a threat stimulus and reflected the defensive and aversive nature of the response ( Brudzynski et al., 1993b ). Thus, the cumu-lated time of growling vocalization appeared to be the best parameter for quantitative mapping of the emo-tional response in the cat’s brain.

Although initially some qualitative mapping attempts were done in the cat’s brain ( Allikmets, 1974 ; Brudzynski et al., 1973 ), a comprehensive quantita-tive mapping of the carbachol-induced response was accomplished more than 20 years later, summarizing responses from 215 injection sites ( Brudzynski, et al., 1995 ). The brain regions from which the response could be induced by a single unilateral dose of 10 μ g of carbachol in unprovoked cats extended along two axes in the brain: (1) longitudinally along the neuraxis from tegmentum, through the hypothalamus to the basal forebrain including nucleus of the diagonal band; and (2) vertically along the fornix, from the medioba-sal hypothalamus to the septum ( Fig. 1 ). This extended strip of tissue showed anatomic specificity but varied response intensity. An intensive response was obtained from many hypothalamic – preoptic and septal areas. Weak responses were recorded from some regions (e.g., from ventromedial hypothalamus, ventral tha-lamus, supraoptic nucleus), or the response could not be induced from some other structures (e.g., from the ventral portion of the posterior hypothalamus, ventral tegmental area, amygdala, large fiber tracks and lateral ventricle) ( Fig. 2 ) ( Brudzynski et al., 1995 ).

It was noted during the mapping study that there was a significant linear negative correlation between the magnitude of the vocalization response and the distance from the injection site to the wall of the third ventricle in the hypothalamus. At the same time, intraventricular injections were ineffective; even those that were done in close proximity to the intra-ventricular ependyma both in the lateral and third ventricle ( Brudzynski et al., 1995 ). It was evident that

the periventricular tissue, also termed periventricular stratum ( Sutin, 1966 ), stretched along the third ven-tricle, and a strip of tissue which continued medially up to the septum were the most sensitive to carbachol stimulation and induced the longest vocalizations.

The muscarinic nature of this response needed then to be reconfirmed locally in the anteromedial hypotha-lamic region, since there were reports that nicotinic antagonists, given in very large doses, could partially or totally antagonize the carbachol-induced response. Carbachol-induced vocalization was reduced by more than 50% by large intracerebral doses of such gangli-onic blocking agents as hexamethonium, tetraethylam-monium, or mecamylamine. Interestingly, very high doses of noradrenaline (50 μ g) injected into the same brain site before carbachol entirely blocked the response as well ( Decsi et al., 1969 ). In addition, d-tubocurar-ine, a nicotinic antagonist which could induce a high-pitched meowing in cats when injected alone ( Decsi and Karmos-V á rszegi, 1969 ), showed an antagonistic effect to the carbachol-induced response. The d-tubocurarine antagonism seemed to be non- competitive, because it occurred even if the d-tubocurarine was injected into the brain site contralateral to the carbachol injection ( Decsi et al., 1969 ).

When low doses, close to equimolar amounts, of the muscarinic antagonists were given intracer-ebrally before carbachol, the muscarinic nature of the response was evident. Carbachol-induced growl-ing vocalization was dose-dependent, could not be antagonized by equimolar mecamylamine, a nicotinic antagonist, but was almost totally antagonized by pre-treatment with equimolar amounts of atropine. At the same time, local injection of physostigmine, which potentiates cholinergic transmission, induced a simi-lar response to that after carbachol ( Brudzynski et al., 1990, 1995 ).

Other studies using two salts of atropine, atropine sulfate, which penetrates the blood – brain barrier, and atropine methyl nitrate, which cannot pene-trate that barrier, provided indirect evidence that the endogenous acetylcholine in the basal forebrain and diencephalon plays a role in naturally occurring emo-tional-aversive responses with growling vocaliza-tion in cats ( Brudzynski et al., 1990 ). A comparable growling vocalization in cats appeared after presen-tation of a dog (but not a cat) or after intracerebral injection of carbachol or physostigmine. The car-bachol-induced response was blocked by systemic atropine sulfate, but was not affected by systemic atropine methyl nitrate ( Brudzynski et al., 1990 ).

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Thus, the central muscarinic cholinergic system was involved in production of growling vocalization and the underlying emotional-defensive response.

III . Quantitative mapping studies of cholinergically-induced vocalization in rats

Despite extensive studies of the effects of intracerebral carbachol in rats for at least 20 years, it was not possi-ble to record vocalization in rats without the aid of a bat detector, which can lower sound frequency to an audi-ble range and reveal the ultrasonic sounds. It was possi-ble, however, to demonstrate the defensive nature of the

response in rats and a number of autonomic changes. Grossman (1972) has found that neither cholinergic agents (carbachol, physostigmine) nor anticholiner-gic agents (atropine, scopolamine) given into the rat brain in crystalline form had any significant influ-ence on shock-induced aggressive behavior or fighting for dominance, and suggested that aggression is not critically dependent on the activity of the cholinergic system. However, results of later studies have demon-strated that intrahypothalamic injections of carbachol or physostigmine in rats have increased the shock-induced defensive fighting, while injection of scopo-lamine reduced this fighting ( Bell and Brown, 1980 ). Thus, the cholinergic agents caused potentiation of the

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Fig. 1. Quantitative map of 215 unilateral injection sites for carbachol (10 μg) in the cat’s brain shown on the parasagittal cross-section 2 mm lateral from the midsagittal plane. The injection sites are marked with symbols proportional to the magnitude of the growling vocalization (cumulative vocalization time over 30 minutes, VOC. TIME [s]). The symbols are listed on the right-hand side margin. The size of the circle corresponds to the magnitude of the vocalization time. The stereotaxic scales are in mm. Selected abbreviations: ACC: nucleus accumbens; ca: commissura anterior; CD: nucleus caudatus; CM: nucleus of centrum medianum; DB: diagonal band of Broca; FF: fields of Forel; fx: fornix; HA: anterior hypothalamic area; HD: dor-sal hypothalamic area; HP: posterior hypothalamic area; HVM: ventromedial nucleus of hypothalamus; LV: lateral ventricle; MB: mammillary bodies; MD: thalamic mediodorsal nucleus; mtt: mammillothalamic tract; 3 N: oculomotor nerve; NCA: nucleus of anterior commissure; NDB: nucleus of the diagonal band; oc: optic chiasm; ON: optic nerve; OT: olfactory tuber-cle; PD: pre-diagonal area; PO: preoptic area; RF: reticular formation; RN: nucleus ruber; RT: reticular nucleus of thalamus; SE: septum; SN: substantia niagra; SO: supraoptic nucleus; TC: tuber cinereum; TVM: ventromedial nucleus of thalamus; VA: ventral anterior nucleus of thalamus; VTA: ventral tegmental area; ZI: zona incerta. Reprinted from Brudzynski et al. (1995) J. Psychiatr. Neurosci., 20: 119 – 132 with permission.

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defensive, but not offensive, behavior in rats, resem-bling the results obtained in cats. This interpretation is consistent with earlier findings that the centrally acting muscarinic antagonist, scopolamine, decreased defen-sive freezing in response to the presence of a cat and

increased the number of approaches to the cat (Plotnik et al., 1974). Also, injections of cholinergic agents into the rat brain (intraventricularly or intrahypotha-lamically) induced autonomic manifestations, such as an increase in blood pressure, heart rate, muscular

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Fig. 2. A summary map of carbachol-induced responses shown on a parasagittal cross-section of the cat brain. (a) The responses are presented in cumulative vocalization as an average per anatomical structure and ranked according to their mag-nitude. (b) Numbers on the horizontal axis in (b) refer to the bold numbers in (a) and correspond to the following structures: 1: septal area (n � 27); 2: medial preoptic area (n � 29); 3: dorsal hypothalamic area and paraventricular nucleus (n � 26); 4: nucleus of commissure anterior (n � 8); 5: perifornical area (n � 19); 6: anterior hypothalamic area (n � 17); 7: nucleus of diagonal band (n � 8); 8: posterior and posterolateral hypothalamic area (n � 17); 9: fields of Forel and zona incerta (n � 16); 10: rostral nucleus ruber (n � 3); 11: ventromedial hypothalamic nucleus (n � 6); 12: ventral thalamic nuclei (n � 7); 13: pre-diagonal area (n � 7); 14: optic chiasm and supraoptic nucleus (n � 9); 15: diagonal band (n � 4); 16: mammillary bodies and ventral tegmental area (n � 2); 17: lateral ventricle (not marked in A, n � 4). Stereotaxic coordinates are in mm. Vertical lines in (b) represent SEMs. Reprinted from Brudzynski et al. (1995) J. Psychiatr. Neurosci., 20: 119 – 132 with permission.

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tremor, hyperthermia, and caused hyperglycemia and changes in the cortical EEG ( George et al., 1966 ; Avery, 1970 ; Crawshaw, 1973 ; Carmona and Slangen, 1974 ; Hoffman and Phillips, 1976 ; Korner and Ramu, 1976 ), suggesting autonomic activation and general arousal.

Using a simple bat detector, Brudzynski and Bihari (1990) reported for the first time that unilateral injec-tion of carbachol (1 μ g) into the anteromedial hypotha-lamic area in the rat induced typical 22 kHz ultrasonic vocalizations (alarm calls) with duration of indi-vidual calls up to 1000 ms. Cholinergically-induced 22 kHz vocalizations from the anterior hypothalamic and preoptic areas did not differ substantially in any of the acoustic parameters from calls evoked natu-rally by hand-touch of na ï ve unhabituated rats or by foot-shock ( Brudzynski et al., 1991b ). Although the duration of single 22 kHz calls was 25% longer in the hand-touch and foot-shock conditions (up to 2,000 ms) than that in carbachol-induced calls (up to 1,500 ms), calls were of substantial duration in all studied situa-tions. These results provided evidence that intracer-ebral carbachol induced typical alarm calls that were known to be emitted predominantly in anticipation of unavoidable aversive stimuli (van der Poel and Miczek, 1991; Blanchard et al., 1992 ; Brudzynski and Ociepa, 1992 ).

Results of these studies have strongly suggested that the rat central cholinergic system is involved in production of 22 kHz alarm calls. The magnitude of the vocal response was dose-dependent and could be antagonized by local pretreatment with equimolar concentrations of muscarinic antagonists ( Brudzynski and Bihari, 1990 ; Brudzynski, 1994 ). Intracerebral pretreatment with an equimolar amount of atropine sulfate decreased the response by 85%. A quantitative functional mapping of the vocal response in the rat brain (at an average effective dose of 1 μ g) revealed a medial cholinoceptive brain system stretched along the periventricular areas from tegmentum to the pre-optic area and up to the septum ( Brudzynski, 1994 ; Dencev et al., 1996 ) ( Fig. 3 ). The strongest responses measured by a cumulated time of vocalization in sec-onds were obtained from the medial preoptic region, anterior hypothalamic area and lateral septal locations ( Brudzynski, 1994 ; Dencev et al., 1996 ). Negligible or no responses were observed in the nucleus of the diag-onal band, anterior commissure, substantia innomi-nata, lateral and particularly far-lateral hypothalamus, ventromedial hypothalamic nucleus, ventral portion of the posterior hypothalamus, medial septal nuclei

and ventricles. This cholinoceptive system showed remarkable homology with that in the cat brain.

Intracerebral carbachol also induced concomi-tant manifestations (other than vocalization) char-acteristic for a defensive behavioral response, including a crouched body posture, lowered head, freezing response and/or decrease in locomotor activ-ity (Brudzynski and Mogenson, 1986). These mani-festations were induced from the same brain regions as the 22 kHz ultrasonic vocalization. Brain mapping of carbachol-induced decrease in locomotor activity revealed a comparable brain system to that mapped for rat vocalization ( Brudzynski et al., 1989 ).

IV . The medial cholinoceptive vocalization strip

The regions from which carbachol could induce 22 kHz vocalization in the rat appeared to be homol-ogous to the system identified in the cat brain for cholinergic induction of growling vocalization ( Brudzynski, 1998, 2001 ). This strip of tissue in both studied species was termed the medial cholinoceptive vocalization strip ( Fig. 4 , stippled area) ( Brudzynski, 1998, 2001 ). It was postulated on the basis of the studies that in addition to anatomical homology, acti-vation of this system is involved in homolog behavio-ral responses in these species. Both growling in cats and alarm calls in rats represent defensive and aver-sive types of vocalization, and both are accompanied by defensive behavioral patterns and autonomic acti-vation. The precise communicative values of growl-ing in cats and 22 kHz calls in rats might be different because of a substantial difference in social organi-zation in these two species. Nevertheless, carbachol-induced vocalization could be induced from homolog brain structures and the released responses were asso-ciated with aversive contexts, threatening stimuli and/or unavoidable danger.

Both , cats ’ growling and rats ’ alarm calls are remarkably prolonged vocalizations. In cats, the devel-oped single growl could last up to 11 seconds while in rats, single call duration reached over 3.9 seconds ( Brudzynski et al., 1993a ). Both cat and rat vocaliza-tions were at the low end of the audible (to humans) frequency range for cats and at the low end of the ultrasonic frequency range for rats. It was also shown that both species responded to the respective vocali-zations in their species-specific way, and consistently showed defensive behavioral patterns ( Blanchard et al., 1991 ; Sales, 1991 ; Brudzynski and Chiu, 1995 ;

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39_P374593_Ch26.indd 272 9/29/2009 1:54:26 PM


Brudzynski, 2001 ; for defensive patterns in cats, see Leyhausen, 1979 ; see also W ö hr and Schwarting, Chapter 4.2 in this volume).

It became apparent from the analysis of the location of the medial cholinoceptive vocalization strip that it represents a widespread terminal field of the ascending cholinergic pathways and the strip closely follows a por-tion of the ascending mesolimbic cholinergic pathways from the laterodorsal tegmental nucleus ( Satoh and Fibiger, 1986 ; Cornwall et al., 1990 ). The terminal field is extensive and initiation of the emotional- defensive response with vocalization required stimulation of large brain regions (with a small dose) within the strip or more localized stimulation with a large dose of the drug ( Brudzynski and Eckersdorf, 1988 ). However, activa-tion of the source of the ascending cholinergic projec-tion in the brainstem could induce this response from a very limited brain region. Such experiments were per-formed on both cats and rats.

Bilateral injection of a low dose of kainic acid into the region of the periaqueductal gray matter (with

spread to the neighboring nuclei) in cats induced an emotional-defensive response with growling vocaliza-tion, while injection of the same dose into the antero -medial hypothalamic area did not induce such a response ( Eckersdorf et al., 1996 ). Similar behavioral responses with growling, howling and hissing vocali-zation were induced in cats from a larger “ defensive region ” of the periaqueductal gray after unilateral injection of kainite and other excitatory amino acids, such as l-aspartate and d,l-homocysteate ( Bandler and Carrive, 1988 ). Comparable microinjections of excita-tory amino acids were performed into the periaqueduc-tal gray matter of rats ( Bandler et al., 1985 ; Bandler and Depaulis, 1988 ). Injections induced a number of behavioral defensive responses; however, the authors did not record ultrasonic vocalizations. Low doses of excitatory amino acids act as neuronal activator and can depolarize neurons within the area of the diffu-sion of the injected agent without affecting axons ( Goodchild et al., 1982 ). These results have suggested that the excitatory amino acids, at least partially,

GI

2 mm

CE

VN

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fr

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NA

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LScc

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AM

MD

HI

AO

OB

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Fig. 4. Parasagittal cross-section of the rat brain 0.9 mm lateral from the midsagittal plane. The medial cholinoceptive vocaliza-tion strip is indicated by a stippled area. Ascending cholinergic projections from the laterodorsal tegmental nucleus (LDT) are superimposed on the diagram and shown by black arrows according to the study by Sato and Fibiger (1986). Selected abbrevi-ations: AH: anterior hypothalamic area; AM: anteromedial thalamic nucleus; AO: anterior olfactory nucleus; BS: bed nucleus of stria terminalis; cc: corpus callosum; CG: central (periaqueductal) gray; cp: superior cerebellar peduncle; DB: horizontal limb of the diagonal band; DM: dorsomedial hypothalamic nucleus; dtb: dorsal tegmental bundle; fr: fasciculus retroflexus; fx: fornix; HI: hippocampal formation; LDT: laterodorsal tegmental nucleus; LS: dorsal portion of the lateral septal nucleus; MD: mediodorsal thalamic nucleus; MM: mammillary nuclei; NA: nucleus accumbens; ot: optic tract; ox: optic chiasm; PIT: pituitary gland; PN: pontine nuclei; PO: medial preoptic area; RN: red nucleus; SF: septofimbrial nucleus; TC: area of the tuber cinereum; TU: olfactory tubercle; VL: ventral portion of the lateral septal nucleus; VM: ventromedial nucleus of the hypothalamus; VP: ventral pallidum; VT: ventromedial thalamic nucleus; VTA: ventral tegmental area; ZI: zona incerta. Reprinted from Brudzynski (2001) Neurosci. Biobehav. Rev., 25: 611 – 617 with permission.

39_P374593_Ch26.indd 273 9/29/2009 1:54:28 PM


could activate tegmental cholinergic neurons with the ascending pathways and induce defensive responses in this way.

The main group of cholinergic cell bodies is local-ized in the laterodorsal tegmental nucleus (Ch6 group), pedunculopontine nucleus (Ch5 group) and some neighboring structures, including the ventral peri -aqueductal gray ( Honda and Semba, 1995 ; Motts et al., 2008 ; Wang and Morales, 2009 ). However, the main ascending projections to the diencephalic and forebrain regions originate in the laterodorsal tegmental nucleus ( Satoh and Fibiger, 1986 ; Hallanger and Wainer, 1988 ; Cornwall et al., 1990 ; Woolf et al., 1990 ) (see Fig. 4 ). Direct injections of an excitatory amino acid, gluta-mate, directly into the laterodorsal tegmental nucleus in the rat induced the most complete and intensive defensive response with ultrasonic alarm calls (22 kHz vocalizations, Brudzynski and Barnabi, 1986 ; Bihari et al., 2003 ). The response was intensive, with a short latency of 15 seconds, which is 12-fold shorter than latency for carbachol-induced 22 kHz calls, and with a faster succession of emitted calls than that after carbachol.

This result was interpreted such that activation of cholinergic neurons of the laterodorsal tegmen-tal nucleus, which have ascending projections to the medial cholinoceptive vocalization strip, caused a widespread release of acetylcholine from the ter-minals within all or most areas of the cholinocep-tive strip, bringing about the fully-blown defensive response with alarm vocalization. In order to provide supportive evidence for this explanation, larger than usual volumes of atropine or scopolamine (muscarinic antagonists) were injected into the medial cholinocep-tive strip to antagonize this response. After direct pre-treatment of the preoptic/anterior hypothalamic areas with atropine or scopolamine, the glutamate-induced alarm vocalization from the laterodorsal tegmental nucleus was significantly reduced ( Brudzynski and Barnabi, 1986 ). A similar experiment was repeated for the lateral septal region, from which carbachol can also release 22 kHz calls. Pretreatment of the lateral septum with scopolamine significantly reduced the defensive response, with alarm calls induced by direct injection of glutamate into the laterodorsal tegmental nucleus ( Bihari et al., 2003 ).

In summary, the medial cholinoceptive vocaliza-tion strip represents a widespread terminal field of the ascending cholinergic projections from the laterodorsal tegmental nucleus. It is not known at present how large a portion of this strip has to be activated to initiate the

behavioral response with vocalization. It could be a small number of neurons in a limited region, or larger pools of neurons spread over a considerable area. This question may be illustrated by a previous experiment on cats with mild kainite lesions. Doses of the kainic acid, which caused limited damage around the injec-tion site, could not decrease the carbachol-induced emotional-defensive response to carbachol, which was subsequently injected into the kainite-treated brain site. However, similar treatment with kainite of the periaqueductal region in the vicinity of cholinergic cell bodies significantly reduced subsequent induc-tion of the response with vocalization ( Eckersdorf et al., 1987, 1996 ). This result indicated that, at the dose level studied, the hypothalamic neurons might be less sensitive to excitotoxic damage than tegmen-tal neurons, and/or even small damage at the tegmen-tal level has much larger functional consequences than comparable damage in the hypothalamus or other local part of the vocalization strip.

V . Function of the medial cholinoceptive vocalization strip

The medial cholinoceptive vocalization strip rep-resents a portion of the ascending brainstem influ-ences on the upper brain. The ascending cholinergic pathways from tegmentum to the diencephalic and forebrain regions form a fragment of brain system associated with the functions of the ascending reticu-lar system. The ascending reticular system has been regarded for a long time as an important regulator of limbic functions ( Moruzzi and Magoun, 1949 ; Shute and Lewis, 1967 ). The mesolimbic cholinergic component of the ascending reticular system ( Lewis and Shute, 1967 ; Shute and Lewis, 1967 ) originates mainly from the laterodorsal tegmental nucleus. This nucleus shows many neurocytological features of the reticular core, with its neurons having long radiating dendrites with overlapping dendritic trees, typical of the reticular formation ( Jones, 1995 ). The ascend-ing cholinergic system appeared to be associated with many physiological states, such as wakefulness, paradoxical sleep, arousal and emotional arousal, including the states associated with emission of alarm vocalizations.

Since the ascending mesolimbic cholinergic sys-tem has diffuse character and innervates widespread areas of the brain, from the internal innervations of the reticular formation itself ( Jones, 1995 ) to the medial

39_P374593_Ch26.indd 274 9/29/2009 1:54:29 PM


cholinoceptive vocalization strip, function of this sys-tem has to be organized in a selective manner, i.e., this system must be able to selectively activate some structures while at the same time not activating other structures. The selective ascending influences may be organized anatomically by distinct pathways (e.g., dorsal and ventral pathway originating from the latero-dorsal tegmental nucleus; Jones, 1995 ), or may depend on differences in the neurochemical substrate (differ-ent subtypes of postsynaptic cholinergic receptors on the target structures), or may depend on both these factors. The cholinergic component of the ascending reticular activating system traveling to the thalamus is mediated by nicotinic and muscarinic receptors (Curro et al., 1991), the reticular activating system controls the dopaminergic neurons by M5 muscarinic and nic-otinic receptors (Forster et al., 2002; Yeomans et al., 2001 ; Wang et al., 2008 ), while effects of choliner-gic input to the medial cholinoceptive vocalization strip could be mediated by M2 muscarinic receptors ( Brudzynski et al., 1991a ). The postsynaptic choliner-gic receptors may also be critical for neuronal postsy-naptic excitatory or inhibitory effects of the ascending cholinergic influences. Thus, the release of acetylcho-line from these terminals in the medial cholinocep-tive vocalization strip was shown to have widespread inhibitory effects on neuronal firing ( Brudzynski et al., 1998 ), while the ascending cholinergic fibers reaching the lateral regions of the basal forebrain, supraoptic nucleus and pituitary region were found to be exci-tatory ( Dreifuss and Kelly, 1970 ; Moss et al., 1972 ; Levine et al., 1986 ; Gribkoff et al., 1988 ; Lin et al., 1993 ; Jones, 2004 ).

Activation of the medial cholinoceptive vocalization strip not only initiates emission of vocalization, but is also associated with the initiation of a negative affec-tive state observed by characteristic manifestations in animals ( Brudzynski, 2007 ). In rats, this state was characterized as anxiety ( Brudzynski and Holland, 2005 ) and production of 22 kHz alarm calls in rats may be treated as an index of a negative affective state ( Knutson et al., 2002 ; Brudzynski, 2007 ). The ascend-ing cholinergic reticular projections are capable of rapid changes in the state of the organism, including its affective component. The positive state was postulated to be initiated by the ascending dopaminergic system with the concomitant 50 kHz vocalization ( Brudzynski, 2007 ; Burgdorf et al., 2008 ). The 50 kHz calls have been reflecting the appetitive state of the organism (see Burgdorf and Moskal, Chapter 6.2 in this volume). Thus, the ascending cholinergic and dopaminergic

systems may work in a mutually exclusive way by a direct or indirect cholinergic – dopaminergic dialog (for details, see Brudzynski, 2007 ).

From the behavioral perspective, it is beneficial for social animals to signal their affective state to conspe-cifics. The best evidence for that comes from experi-ments on rats. Acoustic parameters of 22 and 50 kHz calls are generally non-overlapping ( Brudzynski, 2007 ) and the recipients would have no difficulty in distin-guishing between these signals. It was shown that rats recognize both types of vocalizations and show defen-sive responses to 22 kHz calls ( Blanchard et al., 1991 ; Sales, 1991 ; Brudzynski and Chiu, 1995 ; Brudzynski, 2001 ) and approach responses to 50 kHz calls ( W ö hr and Schwarting, 2007 ; Sadananda et al., 2008 ; see also W ö hr and Schwarting, Chapter 4.2 in this volume).

VI . Summary

The medial cholinoceptive vocalization strip repre-sents a widespread target for the cholinergic portion of the ascending reticular activating system. The ascend-ing cholinergic fibers originate from the laterodorsal tegmental nucleus and terminate in the vocalization strip localized in many medially-located hypotha-lamic/limbic structures. Activation of these ascending pathways and release of acetylcholine in the vocali-zation strip is postulated to be responsible for induc-tion of a negative affective state with concomitant defensive and alarming vocalizations (growling in cats and 22 kHz alarm calls in rats). Thus emission of these vocalizations is indicative of the activity of this ascending cholinergic subsystem and the resulting negative affective state.

Acknowledgments

A portion of presented research results and prepara-tion of this chapter were supported by the research grant from the Natural Sciences and Engineering Research Council of Canada.

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