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JOURNALOFNEUROPHYSIOLOGY Vol. 64, No. 4, October 1990. Printed in U.S.A. Basal Forebrain Projections to Somatosensory Cortex in the Cat KRISTIN E. BARSTAD AND MARK F. BEAR The Center for Neural Science, Brown University, Providence, Rhode Island 02912 SUMMARY AND CONCLUSIONS 1. This investigation was designed to identify the source of cholinergic basal forebrain projections to somatosensory cortex in the cat. 2. Injections of horseradish peroxidase (HRP) into cortical areas 3a, 3b, and 1 after a 36 to 48-h survival period, labeled neurons in the basal forebrain. The distribution of retrogradely labeled neurons was compared with the distribution of cells labeled by choline acetyltransferase immunocytochemistry. Most retrogradely labeled neurons in the basal telencephalon were found on the border between the globus pallidus and adjacent structures. Sometimes labeled neurons were also found in both limbs of the diagonal band of Broca. 3. Excitotoxin lesions of these regions of the basal telencephalon led to a profound depletion of acetylcholinesterase-containing axons in primary somatosensory cortex. 4. These data lay necessary groundwork for tests of the hypothesis that the cholinergic projection modulates experience-dependent modifications in adult cat somatosensory cortex. INTRODUCTION A problem of extraordinary interest concerns the mechanisms by which cortical synapses are modified by sensory experience. The cat striate cortex has proven to be a useful model for this enquiry. As Wiesel and Hubel first showed in 1963, the synaptic organization of cat visual cortex can be readily modified by sensory experience during the first 3 mo of postnatal development. For example, temporary closure of one eyelid in kittens renders most neurons in striate cortex unresponsive to stimulation of the deprived eye (Hubel and Wiesel 1970). This change in ocular dominance seems to require that animals attend to visual stimuli and use vision to guide behavior (Singer 1979, 1982; Singer et al. 1982), prompting the idea that experience-dependent modifications in neocortex depend on the presence of “gating” signals, which convey information about the behavioral state of the animal (Singer 1979). The neural substrate of these gating signals appears to be the noradrenergic projections of the locus coeruleus (Kasamatsu and Pettigrew 1979) and the cholinergic projections of the basal forebrain (Bear and Singer 1986) because destruction of these two projections interferes with normal experiencedependent modifications in the visual cortex (Bear and Singer 1986). An important extension of this idea is to determine whether these modulatory projections play a central role in the modification of neocortex generally or whether their effects are restricted to the visual cortex during early postnatal development. We have therefore turned our attention to another model of cortical plasticity-adult cat somatosensory cortex. It is well documented that the cortical representation of the body surface can be modified by manipulations of the sensory periphery in adult mammals including cats (Kalaska and Pomerantz 1979), raccoons (Rasmusson 1982; Rasmusson and Turnball 1983), rats (Wall and Cusick 1984), and monkeys (Merzenich et al. 1983). As in immature cat visual cortex, experience-dependent modifications of somatosensory cortex appear to be modulated by behavioral state (Merzenich 1987). Dykes (1990) proposed that the cortical cholinergic projection is one neural substrate of this modulation. This hypothesis is based in part on the findings that acetylcholine (ACh) is released in cortex on arousal and sensory stimulation (Celesia and Jasper 1966; Phillis and Chong 1965), and that iontophoretically applied ACh alters neuronal excitability such that cortical neurons become more responsive to peripheral stimulation. Metherate et al. (1987) have found that this enhancement of neuronal responses in somatosensory cortex can last for periods of up to 1 h after cessation of the ACh application, leading to the hypothesis that ACh plays a permissive role in the use-dependent shifts in the adult cortical somatotopic map (Dykes 1990). A direct test of this hypothesis requires that the cortical effects of ACh be eliminated at the same time that somatosensory cortex is challenged to undergo experience-dependent modification. One strategy to deplete cortical ACh involves the destruction of cortically projecting cholinergic neurons with the excitotoxin N-methyl aspartate (NMA) (Bear et al. 1985; Bear and Singer 1986). The application of this method to studies of somatotopic map plasticity requires information about the precise location of the cholinergic neurons projecting to primary somatosensory cortex. The aim of this study was to provide this information and to test the feasibility of destroying the cholinergic projection to somatosensory cortex in the cat. The accompanying articles (Tremblay et al. 1990a,b) used this information to manipulate the release of ACh from cholinergic basal forebrain axons in cat somatosensory cortex. METHODS Experimental design The cholinergic innervation of cat visual cortex appears to be entirely extrinsic in origin, arising largely, if not exclusively, from neurons distributed in the basal telencephalon (Bear et al. 1985). Our strategy in this study was to retrogradely label with horseradish peroxidase (HRP) those basal forebrain neurons that project to somatosensory cortex and to compare this distribution with that of neurons containing choline acetyltransferase (ChAT), the rate-limiting enzyme in the synthesis of ACh. Once the source of the basal forebrain projection to somatosensory cortex was iden- 0022-3077190 $1 SO Copyright 0 1990 The American Physiological Society 1223 1224 K. E. BARSTAD AND M. F. BEAR 14.68 FIG. 1. A, C, E, and G: drawings of coronal sections through a cat basal telencephalon that was processed for choline acetyltransferase immunocytochemistry. Each dot represents a single immunoreactive neuron. Approximate stereotaxic plane ofeach section is indicated (in millimeters anterior to the interaural line). On the righf ofeach panel (B, D. F, and H) is a photomicrograph of a Nissl-stained section adjacent to the one processed for immunocytochemistry. AC, anterior commissure; Ca, caudate nucleus; DBH, horizontal limb of the diagonal band of Broca; DBV, vertical limb of the diagonal band of Broca; F, fornix; GP, globus pallidus; lC, internal capsule; MSN, medial septal nuclei: Put, putamen. BASAL FOREBRAIN PROJECTION IN CAT CORTEX 1225 17.24 tified, we next sought to destroy this projection with stereotaxic injections of NMA. The successof the lesions was monitored by the use of acetylcholinesterase (AChE) histochemistry, as avail- able evidence indicates that this simple method is sufficient to reveal the entire distribution of cholinergic axons in adult cat neocortex (Bear et al. 1985; Stichel and Singer 1987). 1226 K. E. BARSTAD AND M. F. BEAR Gmm 14.8 5mm FIG. 2. Plots of coronal sections through the basal telencephalon of cut C-147 showing the location of HRP-containing neurons after a large unilateral pressure injection into somatosensory cortex (indicated by cross-hatched regions in insets). See Fig. 1 legend for abbreviations. ChA T experiment One cat was used to prepare an atlas of ChAT immunoreactive neurons in the basal forebrain. This animal was deeply anesthe- tized with pentobarbital sodium and perfused through the ascending aorta with saline followed by 2 1 of fixative and, finally, 2 1 of 0.1 M sodium phosphate buffer (pH 7.4) containing 20% sucrose. The ChAT fixative was 4% paraformaldehyde in 0.1 M phosphate BASAL FOREBRAIN PROJECTION IN CAT CORTEX 1227 . 16.5 16.1 c 149 5mm FIG. 3. Plots of coronal sections through the basal forebrain of cat C-149 showing the location of HRP-containing neurons after small iontophoretic injections into somatosensory cortex (indicated by cross-hatched regions in the dorsal reconstruction). See legend of Fig. 1 for abbreviations. buffer (pH 7.4) and, in the first liter only, 0.1% glutaraldehyde. The brain was removed and stored in 20% sucrose at 4OC. The brain was frozen by submersion in 2-methyl butane at -50°C and cut in the coronal plane at 50 pm. One-half of the tissue sections were reacted for ChAT immunocytochemistry and the other half were Nissl stained. The immunocytochemical pro- cedure was a modification (Stichel and Singer 1987) of the peroxidase-antiperoxidase (PAP) method (Sternberger 1979). First, the tissue was incubated for 5 min in 10% methanol in 3% H202 to quench endogenous peroxidases. Next, the tissue was washed thoroughly with phosphate buffer and incubated overnight in rat anti-ChAT in a vehicle containing 0.5% triton X- 100, 2% bovine 1228 K. E. BARSTAD serum albumin, 20% normal rabbit serum, and 5% sucrose in 0.1 M phosphate buffer. The ChAT antibody was a gift of Dr. Felix Eckenstein (Eckenstein and Thoenen 1982) and was kindly provided by Dr. Ford Ebner. The following day the sections were thoroughly rinsed in buffer and incubated for 90 min in rabbit antirat IgG dissolved in the same vehicle used for the primary antibody. The tissue was washed again in buffer and incubated for 90 min in rat PAP. After another extensive wash, the sections were reacted for 20 min in a solution containing 0.05% diaminobenzidene and 0.01% HzOz. The sections were washed a final time, mounted onto microscope slides, dehydrated in alcohols, cleared in xylene, and coverslipped. HRY experiments Ten adult cats were anesthetized with intravenously administered pentobarbital sodium and placed in a stereotaxic instrument. A large craniotomy was performed to expose the cortex lying between the fork of the ansate sulcus and the cruciate sulcus. Multiple injections of lo-30% HRP were made into the somatosensory cortex - 1 mm below the pia either by pressure injection AND M. F. BEAR by the use of a Hamilton microliter syringe (0.1-0.5 ~1) or by iontophoresis with the use of a glass micropipette (tip diameter, -40 pm; 3-4 PA for 15-20 min). The bone flap was replaced, and the fascia and scalp were sutured closed. After a survival period of 2 days, the animals were reanesthetized with pentobarbital sodium and perfused through the ascending aorta with saline followed by fixative consisting of 1% paraformaldehyde and 1.25% glutaraldehyde in 0.1 M phosphate buffer (pH 7.4). The fixative was followed by ice cold phosphate buffer containing 10% sucrose. The brains were removed from the skull, frozen by submersion in 2-methyl butane at -5O”C, and sectioned in a cryostat at 40 pm in the coronal plane. The tissue sections were reacted for HRP histochemistry by the use of Mesulam’s (1978) procedure as described previously (Bear et al. 1985). Basal forebrain lesions and AChE histochemistry Four adult cats were anesthetized with intravenously administered pentobarbital sodium and placed in a stereotaxic instrument. The needle of a Hamilton microliter syringe was lowered into the regions of the basal telencephalon that the previous HRP experiments had shown to project to somatosensory cortex. l- to FIG. 4. A: ChAT-immunoreactive neurons in the regionimmediatelyventral to the globuspallidus. B: HRP-labeledcells(darkly stained) in the same region after injections into somatosensorycortex. This tissue was lightly counterstainedwith Cresylviolet. Sections photographedin A and Bare at approximately the same coronal plane (-A14.7 mm). BASAL FOREBRAIN PROJECTION 5-~1injections of NMA (50 pg/pl) in saline were made at these locations. The animals were allowed to survive for 1 wk before being reanesthetized and perfused through the ascending aorta with 10% phosphate-buffered Formalin (pH 7.4). The brains were removed and sectioned in a cryostat at 40 pm in the coronal plane. These sections were reacted for AChE by the use of a modification of Jacobowitz and Creed’s (1983) procedure as described in detail by Bear et al. (1985). RESULTS Distribution ofChAT-containing neurons in cat basal telencephalon The location of ChAT-immunoreactive neurons was carefully plotted onto drawings of the basal forebrain and compared to adjacent N&l-stained sections (Fig. 1). Intensely immunoreactive interneurons were consistently observed in the caudate and putamen in all sections. In addition, labeled neurons were observed scattered within the substantia innominata and internal capsule. At coronal planes between the optic chiasm and anterior commissure (Fig. 1, A-D), a prominent collection of immunoreactive neurons was found in the semicircular border zone lying between the globus pallidus and structures lateral and ventral. ChAT’ neurons were also found in the medial septal nucleus at these levels. At coronal planes further anterior (Fig. 1, E-H), most ChAT+ cells were concentrated in the horizontal and vertical limbs of the diagonal band of Broca, in addition to the substantia innominata and internal capsule. Distribution of HRP-backjlled into somatosensory cortex neurons after injections Injections of HRP into the somatosensory cortex led to retrograde transport by neurons in the ventral posterior I229 IN CAT CORTEX thalamus, dorsal claustrum, and basal forebrain. The labeled cells in the basal forebrain fell predominantly within a neatly circumscribed area. After large cortical injections, some neurons were observed scattered within the internal capsule and the vertical and horizontal limbs of the diagonal band; however, most retrogradely labeled cells were found clustered in an arc along the border zone between the globus pallidus and putamen, laterally, and substantia innominata ventrally (Fig. 2). Decreasing the size of the cortical injection, as was done in later experiments by the use of iontophoresis, diminished the relative number of HRP-containing cells in the basal forebrain (Fig. 3), but the distribution of labeled neurons remained similar. Again, the highest density of stained neurons occurred in the region immediately lateral and ventral to the globus pallidus. As illustrated in Fig. 4, there is a close correspondence between the distribution and morphology of cortically projecting neurons and ChAT-immunoreactive cells in the region ventrolateral to the globus pallidus. This correlation suggests that this region is a likely source of cholinergic projections to somatosensory cortex. This hypothesis was tested by making excitotoxin lesions in this region and searching for a depletion of AChE-containing axons in somatosensory cortex. Eflects of basal,forebrain somatosensory cortex lesions on AChEi axons in There are some laminar differences in the distribution of AChE+ axons in cat somatosensory cortex (Fig. 5, A and B). For example the highest density of AChE+ axons occurs in layer I, and the lowest density occurs in upper layer IV and layer V. Nonetheless, all layers are richly innervated by FIG. 5. A: Nissl cytoarchitectureof somatosensory cortexm a normal cat. B: section adjacent to that shown in A stained for acetylcholinesterase to reveal the normal pattern and density of AChE’ axons. C: section through somatosensory cortex of cat C-153, processed for AChE histochemistry. C-l.53 recewed a unilateral lesion ofthe basal telencephalon 7 days earlier (lesionreconstructedm Fig. 6). Note the striking depletion of AChE+ axons. 1230 K. E. BARSTAD AChEcontaining axons. This pattern of AChE-containing axons is similar to that observed in cat striate cortex (Bear et al. 1985). If these AChE+ fibers reflect a cholinergic projection from the basal telencephalon, our HRP experiments sug- AND M. F. BEAR gest that they arise from neurons located in the substantia innominata, diagonal band of Broca, and the ventrolateral border of the globus pallidus. To test this hypothesis, we made lesions of the basal telencephalon with the excitotoxin NMA. 18.50 c 153 1 cm l& nn I KJ FIG. 6. Reconstruction of a lesion in the basal telencephalon of cat C-153 after 2 injections of the excitotoxin IVmethyl-aspartate. Cross-hatching indicates regions of cell loss; stars indicate 2 injection sites. See Fig. 1 legend for abbreviations. BASAL FOREBRAIN PROJECTION The largest of these basal forebrain lesions is reconstructed in Fig. 6. This lesion was made by two NMA injections, one targeting the region surrounding the globus pallidus (from the interaural line in mm: A. 15, L. 7, D. 8) and the other targeting the horizontal limb of the diagonal *band of Broca (A. 16, L. 3, D. 7). As illustrated in Fig. 5 (C), this lesion produced a striking depletion of AChE+ axons in all layers. Smaller lesions confined to the area of the globus pallidus also depleted cortical AChE but not as extensively. Taken together these experiments demonstrate that the vast majority of cholinesterase containing axons in cortex arise from an identifiable region of the basal telencephalon and validate the utility of AChE histochemistry to assessthe integrity of the cortical cholinergic projection. DISCUSSION Origin of the cholinergic projection to somatosensory cortex in the cat The aim of this study was to identify the location of neurons in the basal telencephalon that project to somatosensory cortex in the cat. Our retrograde transport experiments revealed that basal forebrain projections to somatosensory cortex arise from neurons that are scattered widely in the basal forebrain. However, the major source of basal forebrain projections to somatosensory cortex appears to be the region immediately ventral-lateral to the globus pallidus. This finding is consistent with a brief report by Ribak and Kramer (1982) that AChE-containing neurons in this region project directly to motor cortex in the cat. Several lines of evidence suggest that this projection is cholinergic. First, immunocytochemical experiments show a high density of large neurons containing ChAT in this region of the basal forebrain. Second, excitotoxin lesions of the globus pallidus severely deplete somatosensory cortex of AChE-positive axons. Third, Tremblay et al. (1990a,b) find that electrical stimulation of this region of the basal forebrain evokes responses in cortical area 3b that can be blocked by the muscarinic cholinergic antagonist atropine. Taken together, these data support the hypothesis that the basal forebrain provides a major cholinergic projection to somatosensory cortex in the cat. A combination of lesion and histochemical studies led to a similar conclusion concerning the source of the cholinergic innervation of visual cortex in the cat (Bear et al. 1985). However, the visual cortical projections appear to arise mainly from the horizontal limb of the diagonal band of Broca and from neurons embedded within the internal capsule (Bear et al. 1985; Bear and Singer 1986) rather than from the regions identified here. Few neurons in the vicinity of the globus pallidus are labeled after HRP injections into area 17. Thus it appears that a crude topography exists in the neocortical projections of the basal forebrain in the cat. Lesion experiments reveal that most, if not all, of the AChE-positive axons in both visual and somatosensory cortex arise from the basal telencephalon. In cat visual cortex the elegant immunocytochemical studies of DeLima and Singer (1986) and Stichel and Singer (1987) have al- IN CAT CORTEX 1231 lowed a direct comparison of the distribution of axons containing ChAT and AChE. The correspondence appears to be excellent, suggesting that the large majority of AChEpositive axons in the visual cortex are in fact cholinergic. This encourages us to believe that AChE histochemistry in somatosensory cortex reveals the full complement of cholinergic axons arising from the basal forebrain, although ChAT immunocytochemistry will be required to establish this definitively. Comparisons with other species The organization of basal forebrain projections to primary somatosensory cortex in the cat is similar to that described for the rat and monkey (Johnston et al. 198 1; Lehman et al. 1980; McKinney et al. 1983; Mesulam et al. 1983; Saper 1984). For example, in the rat the cholinergic projection to parietal cortex arises from neurons immediately ventral to the globus pallidus, whereas the projection to occipital cortex arises from cells in the horizontal limb of the diagonal band of Broca (McKinney et al. 1983). In the rhesus monkey the basal forebrain projection to primary somatosensory cortex originates entirely from the nucleus basalis of Meynert (Mesulam et al. 1983). The primate nucleus basalis can be identified in Nissl-stained sections on the basis of its large, darkly stained neurons, and lies immediately ventral to the caudal globus pallidus (Heimer et al. 1989). No homology to the nucleus basalis has been generally recognized in the cat (Berman and Jones 1982), but the present results support the interpretation of Grofova ( 1970) that the large cells in the dorsolateral aspect of cat substantia innominata (Fig. 1) can be regarded as homologous to the primate nucleus basalis. Functional implications The wide distribution of cortically projecting basal forebrain neurons raises the question of whether different parts of the basal forebrain cholinergic “system” have different patterns of afferent connectivity. It remains an intriguing possibility that the cortically projecting cholinergic basal forebrain actually consists of a series of subsystems that are specialized to respond under different behavioral conditions. In any case, the scattered distribution of neurons with projections to somatosensory cortex presents a technical challenge for producing complete lesions of the cortical cholinergic inputs or for any other manipulations of these neurons. Even the largest lesions in this study, which included a significant fraction of the substantia innominata, globus pallidus, putamen, and adjacent structures, never fully depleted the somatosensory cortex of AChEpositive axons. Nonetheless, it is likely that the degree of depletion attained after these lesions is sufficient to help elucidate cholinergic contributions to cortical function. For example, excitotoxin lesions of cat basal telencephalon have been found to reduce the metabolic activity evoked in somatosensory cortex by repetitive tactile stimulation (Juliano et al. 1988), an effect that is also mimicked by topical application of atropine. This study provides the necessary groundwork for direct manipulations of the cholinergic basal forebrain projection 1232 K. E. BARSTAD to somatosensory cortex in the cat. In the accompanying papers, Tremblay et al. (1990a,b) report that electrical stimulation of the region we have identified as the cat nucleus basalis leads to facilitation of responses evoked in area 3b by glutamate iontophoresis and tactile stimulation (see also Rasmusson and Dykes 1988). These effects are mimicked by iontophoretically applied ACh (Metherate et al. 1987) and are antagonized by the muscarinic receptor blocker atropine. Together these results support the hypothesis that the basal forebrain exerts a generally facilitatory influence over area 3b and that this cholinergic projection can be regarded as a critical component of the reticular activating system (reviewed by Dykes 1990; Singer 1979). Furthermore, the long-lasting nature of the facilitation after basal forebrain stimulation suggests that this cholinergic projection can powerfully modulate experience-dependent modifications in the adult cerebral cortex. The authors thank Dr. I. Matjucha for assistance on aspects of this study. This work was supported by ONR contract NO00 14-8 l-K0 136 and a Sloan Foundation fellowship. Address for reprint requests: R. W. Dykes, Dept. of Physiology, Pavillon Principal, Universite of Montreal, C.P. 6 128, succ. A, Montreal, Quebec H3C 357, Canada. 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