Invited Symposium: Role of the Basal Forebrain Neurons in Cortical Activation and Behavioural State Regulation
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Summary of present knowledge
In the last 20 years, a number of avenues of research have converged on the idea that acetylcholine, originating from the projection neurons of the basal forebrain, can induce long-lasting changes in cerebral cortical function. Consistent with this view are the following (A1-A5):
A1) Acetylcholine applied directly onto cortical neurons induces long-lasting changes. This was first shown by Woody et al. (1978) who measured changes in membrane resistance and found an increase in resistance lasting up to 1.5 hours when microiontophoretically applied ACh was paired with intracellular depolarization. Metherate et al. (1987) found similar enhancement of the response to cutaneous stimulation after this was paired with ACh application. Similar changes have been demonstrated in auditory cortex, for example when pairing ACh with glutamate depolarization (Cox et al., 1994).
A2) Pairing of basal forebrain stimulation with sensory input also produces enhanced responding to the sensory input. This has been demonstrated in somatosensory cortex (Rasmusson and Dykes, 1988; Tremblay, 1990; Webster et al., 1991; Howard and Simons, 1994) and in auditory cortex (Edeline et al., 1994; Bakin and Weinberger, 1996; Bjordahl et al., 1998) using both single unit and evoked potential techniques. The study by Bjordahl et al. is particularly interesting because it was carried out on awake animals and demonstrated changes lasting 24 hours.
A3) Electrical stimulation of the basal forebrain (using parameters similar to those used in the enhancement experiments) produces a large increase in extracellular ACh, indicative of effective release from the cholinergic terminals (Casamenti et al., 1986; Kurosawa et al., 1989; Rasmusson et al., 1992).
A4) Associative learning induced by paired stimulation of whiskers and measured electrophysiologically can be blocked by administration of anticholinergic drugs (Delacour et al., 1990; Maalouf et al., 1998) and by selective cholinergic basal forebrain lesions using the immunotoxin 192 IgG (Baskerville et al., 1997; Sachdev et al., 1998). Other studies have looked at metabolic indices of functional organization, for example after peripheral denervation, and also found impaired plasticity after basal forebrain lesions (Juliano et al., 1991).
A5) Behavioral measures of learning have also shown impairments following cholinergic blockade or basal forebrain lesions. A particularly relevant study found impaired performance in sensory discrimination learning after ibotenic acid lesions (Jacobs and Juliano, 1995). However the nonselectivity of ibotenic acid and other neurotoxins has been severely criticized (Dunnett et al., 1991; Fibiger, 1991).
Drug experiments in awake animals are often ambiguous for two reasons:
one is that the cerebral cortex may not be the crucial structure in a particular form of learning;
the other is that systemically administered drugs could be having their main effect at subcortical cholinergic synapses as well as, or instead of, within the cortex. In fact two forms of learning that have often been shown to be impaired by antimuscarinic drugs are spatial learning and passive avoidance learning which clearly involve the hippocampus and amygdala, respectively, more than the cerebral cortex.
Unanswered Questions
Given the numerous studies and different approaches that are consistent with a cholinergic involvement in plasticity within sensory cortices, it is worth directing our attention to questions about this phenomenon that are unanswered (B1-B6):
B1) Have other, non-cholinergic, possibilities been eliminated? The clear demonstration in recent years that there are GABAergic and other non-cholinergic projections from basal forebrain to cerebral cortex (Gritti et al., 1997) raises the possibility that basal forebrain can produce plasticity via other neurons than the cholinergic ones. The GABAergic projection could produce parallel effects as it preferentially innervates intracortical GABAergic interneurons (Freund and Meskenaite, 1992). This could contribute to long-lasting enhancement by contributing to depolarization of pyramidal neurons via a disinhibition. While there is no evidence of a long-term changes in the GABAergic synapses at present, it is conceivable that GABA-B receptors might provide an avenue for such changes. The implications of the GABAergic basal forebrain to cortex pathway need to be explored. Another complication is that ACh itself may excite some cortical interneurons and inhibit others (Xiang et al., 1998).
B2) Have other non-cortical sites for change been eliminated? Projections from basal forebrain to other structures, in particular the thalamus (Levey et al., 1987), may be partly or totally responsible for some of these effects. This has been shown to be a serious complication in deciphering the change in cortical EEG following basal forebrain stimulation (see Steriade’s contribution to this symposium). The ease with which ACh release and EEG activation can be dissociated (Rasmusson et al., 1996) may largely be due to these multiple controls within the sensory systems. One type of experiment that is particularly useful in avoiding this complication is that of Metherate and Ashe (1991) who examined pairing of basal forebrain stimulation with electrical stimulation of the thalamus.
B3) How would this cholinergic mechanism for plasticity work in the real brain? In order for the basal forebrain cholinergic neurons to "control" this type of plasticity in real life, there must be at least two states, a “Plasticity -ON” and a “Plasticity-OFF” state. What is different about the behavior of cholinergic neurons during the Plasticity-ON vs. the Plasticity-OFF states? Some studies have noted the increases in firing rates of basal forebrain neurons in relation to reward (Richardson and DeLong, 1986; Rigdon and Pirch, 1986). Others have described different firing patterns, bursting and tonic, in cholinergic neurons (Khateb et al., 1992; Nuñez, 1996). While the amount of ACh released in the cortex is clearly dependent on the stimulation frequency (Rasmusson, et al., 1992), the consequences of bursting vs. non-bursting activity on ACh release have not been addressed.
(B4) A related question is what information is the basal forebrain neuron receiving that might turn them from the Plasticity-OFF to the Plasticity-ON state? Inputs using neurotensin are interesting as they can induce bursting in basal forebrain neurons (Alonso et al., 1994), but there are many other inputs including the pedunculopontine nucleus, the locus coeruleus and the raphe nuclei (Détári et al., 1997). The circuitry of projection and local neurons within the basal forebrain is largely unknown, as is the question of how the various inputs might be integrated by the basal forebrain cholinergic neurons.
(B5) What is the specificity of basal forebrain neurons and how much specificity is needed to carry out this putative role in plasticity? In general terms it might be asked whether there is sufficient regional specificity that the basal forebrain can turn on plasticity within only one sensory modality? There is evidence that ACh release can increase more in one cortical area than in another in a predictable pattern (Collier and Mitchell, 1966; Rasmusson and Szerb, 1976; Butt et al., 1997; Jiménez-Capdeville et al., 1997), although some increase appears to occur across the entire cortex. A more difficult question is whether, within a sensory cortical region, there is sufficient specificity to permit “useful” changes? For example, if the entire somatosensory cortex is flooded with ACh, will this not produce enhancement of all inputs to SI?
Possibly the specificity is entirely controlled by the sensory input, e.g. those sensory neurons that are most active would show relatively greater plasticity than the less active inputs and could therefore outdistance their competitors. Another concern is created by the relatively slow time course of ACh effects at a cellular level (Krnjevic et al., 1971); in a sensory discrimination paradigm, for example, both positive and negative conditioned stimuli may occur within a fairly short interval. For a cholinergic mechanism to account for the observed enhancement of response to only one of the stimuli, the postsynaptic effects of ACh be shorter than any interval between the two stimuli. While the slow-time course of ACh action may be an artifact of the microiontophoretic technique, it illustrates how poorly we understand the intracellular events (both pre- and post-synaptic) that might be responsible for the induction and the maintenance of the enhanced response.
(B6) Finally, one must ask whether ACh is involved in all forms of cortical plasticity or, if it is not, what forms is it involved in and what do these have in common? Studies in which ACh release has been measured during behavioral paradigms have not been very successful in defining a single “function” that is consistently related to increased release. A variety of terms including, but not limited to, learning, selective attention, response inhibition, novelty, reinforcement, and sensory discrimination have been applied to these tasks (Rasmusson and Szerb, 1976; Inglis et al., 1994; Inglis and Fibiger, 1995; Acquas et al., 1996; Orsetti et al., 1996; Butt, et al., 1997; Giovannini et al., 1998). It seems likely that there is no unitary function that fits all of these experiments (Fibiger, 1991). Nevertheless, the use of selective cholinergic lesions may at least allow us to make empirical decisions about which examples of plasticity are dependent on cholinergic innervation and therefore direct our attention towards those. Part of the solution will be to avoid the all encompassing term “plasticity” and recognize that the different examples of plasticity may well use different mechanisms. While this seems like a truism, it is all too easy to over-generalize from one experiment, utilizing a particular paradigm, to try to account for all plastic phenomena.
REFERENCES
Acquas, E., C. Wilson, and H.C. Fibiger (1996) Conditioned and unconditioned stimuli increase frontal cortical and hippocampal acetylcholine release: Effects of novelty, habituation, and fear. J. Neurosci. 16: 3089-3096.
Alonso, A., M.-P. Faure, and A. Beaudet (1994) Neurotensin promotes oscillatory bursting behavior and is internalized in basal forebrain cholinergic neurons. J. Neurosci. 14: 5778-5792.
Bakin, J.S., and N.M. Weinberger (1996) Induction of a physiological memory in the cerebral cortex by stimulation of the nucleus basalis. Proc. Natl. Acad. Sci. USA 93: 11219-11224.
Baskerville, K.A., J.B. Schweitzer, and P. Herron (1997) Effects of cholinergic depletion on experience-dependent plasticity in the cortex of the rat. Neuroscience 80: 1159-1169.
Bjordahl, T.S., M.A. Dimyan, and N.M. Weinberger (1998) Induction of long-term receptive field plasticity in the auditory cortex of the waking guinea pig by stimulation of the nucleus basalis. Behav. Neurosci. 112: 467-479.
Butt, A.E., G. Testylier, and R.W. Dykes (1997) Acetylcholine release in rat frontal and somatosensory cortex is enhanced during tactile discrimination learning. Psychobiology 25: 18-33.
Casamenti, F., G. Deffenu, A.L. Abbamondi, and G. Pepeu (1986) Changes in cortical acetylcholine output induced by modulation of the nucleus basalis. Brain Res. Bull. 16: 689-695.
Collier, B., and J.F. Mitchell (1966) The central release of acetylcholine during stimulation of the visual pathway. J. Physiol. 184: 239-254.
Cox, C.L., R. Metherate, and J.H. Ashe (1994) Modulation of cellular excitability in neocortex: muscarinic receptor and second messenger-mediated actions of acetylcholine. Synapse 16: 123-136.
Delacour, J., O. Houcine, and J.C. Costa (1990) Evidence for a cholinergic mechanism of "learned" changes in the responses of barrel field neurons of hte awake and undrugged rat. Neurosci. 34: 1-8.
Détári, L., K. Semba, and D.D. Rasmusson (1997) Responses of cortical EEG-related basal forebrain neurons to brainstem and sensory stimulation in urethane-anesthetized rat. Eur. J. Neurosci. 9: 1153-1161, 1997.
Dunnett, S.B., B.J. Everitt, and T.W. Robbins (1991) The basal forebrain-cortical cholinergic system: interpreting functional consequences of excitotoxic lesions. Trends Neurosci. 14: 494-501.
Edeline, J.-M., B. Hars, C. Maho, and E. Hennevin (1994) Transient and prolonged facilitation of tone-evoked responses induced by basal forebrain stimulations in the rat auditory cortex. Exp. Brain Res. 97: 373-386.
Fibiger, H.C. (1991) Cholinergic mechanisms in learning, memory and dementia: a review of recent evidence. Trends in Neurosci. 14: 220-223.
Freund, T.F., and V. Meskenaite (1992) Gamma-aminobutyric acid-containing basal forebrain neurons innervate inhibitory interneurons in the neocortex. Proc. Nat. Acad. Sci. USA 89: 738-742.
Giovannini, M.G., L. Bartolini, S.R. Kopf, and G. Pepeu (1998) Acetylcholine release from the frontal cortex during exploratory activity. Brain Res. 784: 218-227.
Gritti, I., L. Mainville, M. Mancia, and B.E. Jones (1997) GABAergic and other nonchoinergic basal forebrain neurons, together with cholienrgic neurons, project to the mesocortex and isocortex in the rat. J. Comp. Neurol. 383: 163-177.
Howard, M.A., and D.J. Simons (1994) Physiologic effects of nucleus basalis magnocellularis stimulation on rat barrel cortex neurons. Exp. Brain Res. 102: 21-33.
Inglis, F.M., J.C. Day, and H.C. Fibiger (1994) Enhanced acetylcholine release in hippocampus and cortex during the anticipation and consumption of a palatable meal. Neuroscience 62: 1049-1056.
Inglis, F.M., and H.C. Fibiger (1995) Increases in hippocampal and frontal cortical acetylcholine release associated with presentation of sensory stimuli. Neuroscience 66: 81-86.
Jacobs, S.E., and S.L. Juliano (1995) The impact of basal forebrain lesions on the ability of rats to perform a sensory discrimination task involving barrel cortex. J. Neurosci. 15: 1099-1109.
Jiménez-Capdeville, M.E., R.W. Dykes, and A.A. Myasnikov (1997) Differential control of cortical activity by the basal forebrain in rats: a role for both cholinergic and inhibitory influences. J. Comp. Neurol. 381: 53-67.
Juliano, S., W. Ma, and D. Eslin (1991) Cholinergic depletion prevents expansion of topographic maps in somatosensory cortex. Proc. Natl. Acad. Sci. USA 88: 780-784.
Khateb, A., M. Mühlethaler, A. Alonso, M. Serafin, L. Mainville, and B.E. Jones (1992) Cholinergic nucleus basalis neurons display the capacity for rhythmic bursting activity mediated by low-theshold calcium spikes. Neuroscience 51: 489-494.
Krnjevic, K., R. Pumain, and L. Renaud (1971) The mechanism of excitation by acetylcholine in the cerebral cortex. J. Physiol. Lond. 215: 247-268.
Kurosawa, M., A. Sato, and Y. Sato (1989) Stimulation of the nucleus basalis of Meynert increases acetylcholine release in the cerebral cortex in rats. Neurosci. Lett. 98: 45-50.
Levey, A.I., A.E. Hallanger, and B.H. Wainer (1987) Cholinergic nucleus basalis neurons may influence the cortex via the thalamus. Neurosci. Lett. 74: 7-13.
Maalouf, M., A.A. Miasnikov, and R.W. Dykes (1998) Blockade of cholinergic receptors in rat barrel cortex prevents long-term chagnes in the evoked potential during sensroy preconditioning. J. Neurophyisol. 80: 529-545.
Metherate, R., N. Tremblay, and R.W. Dykes (1987) Acetylcholine permits long-term enhancement of neuronal responsiveness in cat primary somatosensory cortex. Neuroscience 22: 75-81.
Nuñez, A. (1996) Unit activity of rat basal forebrain neurons: Relationship to cortical activity. Neuroscience 72: 757-766. Orsetti, M., F. Casamenti, and G. Pepeu (1996) Enhanced acetylcholine release in the hippocampus and cortex during acquisition of an operant behavior. Brain Res. 724: 89-96.
Rasmusson, D., and J.C. Szerb (1976) Acetylcholine release from visual and sensorimotor cortices of conditioned rabbits: the effects of sensory cuing and patterns of responding. Brain Res. 104: 243-259.
Rasmusson, D.D., K. Clow, and J.C. Szerb (1992) Frequency-dependent increase in cortical acetylcholine release evoked by stimulation of the nucleus basalis magnocellularis in the rat. Brain Res. 594: 150-154.
Rasmusson, D.D., and R.W. Dykes (1988) Long-term enhancement of evoked potentials in cat somatosensory cortex produced by co-activation of the basal forebrain and cutaneous receptors. Exp. Brain Res. 70: 276-286.
Rasmusson, D.D., J.C. Szerb, and J.L. Jordan (1996) Differential effects of a-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptor antagonists applied to the basal forebrain on cortical acetylcholine release and EEG desynchronization. Neuroscience 72: 419-427.
Richardson, R.T., and M.R. DeLong (1986) Nucleus basalis of Meynert neuronal activity during a delayed response task in monkey. Brain Res. 399: 364-368.
Rigdon, G.C., and J.H. Pirch (1986) Nucleus basalis involvement in conditioned neuronal responses in the rat frontal cortex. J. Neurosci. 6: 2535-2542.
Sachdev, R.N.S., S.-M. Lu, R.G. Wiley, and F.F. Ebner (1998) Role of the basal forebrain cholinergic projection in somatosensory cortical plasticity. J. Neurophysiol. 79: 3216-3228.
Tremblay, N., Warren, R.A. and Dykes, R.W. (1990) Electrophysiological studies of acetylcholine and the role of the basal forebrain in the somatosensory cortex of the cat. II. Cortical neurons excited by somatic stimuli. J. Neurophysiol. 64: 1212-1222.
Webster, H.H., U.-K. Hanisch, R.W. Dykes, and D. Biesold (1991) Basal forebrain lesions with or without reserpine injection inhibit cortical reorganization in rat hindpaw primary somatosensory cortex following sciatic nerve section. Somatosens. Motor Res. 8: 327-346.
Woody, C.D., B.E. Swartz, and E. Gruen (1978) Effects of acetylcholine and cyclic GMP on input resistance of cortical neurons in awake cats. Brain Res. 158: 373-395.
Xiang, Z., J.R. Huguenard, and D.A. Prince (1998) Cholinergic switching within neocortical inhibitory networks. Science 281: 985-988.
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