Role of the Basal Forebrain Neurons in Cortical Activation and Behavioural State Regulation

Martin Sarter
sarter.2@osu.edu

Thank you very much for your questions which, in fact, refer directly to some of the more important and critical components of our thinking about the functions of cortical ACh.

With respect to your first question, let us say first that we agree with you entirely that attributions of functions in terms of "arousal" or "cortical activation" do not present a conflict. However, as we tried to point out in this short paper (and as was discussed more extensively by others - see references), "arousal" does not represent a very useful scientific theory or construct (for details see the paper). We also agree with you that the specific functions of BF projections during the performance in attentional tasks and during certain aspects of the sleep-wake cycle, particularly during REM sleep, may overlap. The task is to define specifically the information processing mediated via these projections during wakefulness, under conditions of increased demands on attentional functions, and during REM sleep. It is difficult to see how descriptions in terms of "arousal" add to such investigations that aim at more precise formulations of brain-behavior relationships.

As to your question about the region-(non)specificity of cortical ACh efflux and the functional implications of the possibility that cortical ACh efflux is regulated cortex-wide in a rather global manner, we need to say first that the available evidence, while pointing to a rather global regulation of cortical ACh release, remains limited. Although the afferent regulation of basal forebrain neurons does not seem to suggest the degree of topographic organization that one would expect from a system that allows the activation of specific subgroups of basal forebrain neurons innervating individual cortical areas (see the discussion in Sarter & Bruno 1998), we cannot exclude that under certain conditions, such a cortically-restricted modulation of cortical ACh efflux occurs (e.g., as a result of interactions with thalamic or associational inputs which may modulate presynaptic mechanisms of ACh release). However, the available evidence in support of such a possibility is scarce, and our own data (Himmelheber et al. 1998) as well as other studies (cited in Himmelheber et al.) do not support the hypothesis that ACh efflux is regulated in an area-specific manner.

As you refer to Rasmusson's perspective on this issue (see his contribution to this symposium) he summarizes some of the available data and concludes that "there is evidence that ACh release can increase more in one cortical area than in another in a predictable pattern…although some increase appears to occur across the entire cortex". His conclusion is based mostly on recent data by Jimenez-Capdeville et al. 1997 which show some differences in the levels of changes in ACh release from different cortical areas but which do not form the basis for the conclusion that changes in cortical ACh efflux is cortical area-selective. Thus, in our view, these data, as well as our own findings (Himmelheber et al. 1998) certainly agree with Rasmusson's conclusion. As already stressed, however, the available evidence is insufficient to answer conclusively this question, and we should also not forget that our methods to monitor ACh release in vivo suffer from several limitations (e.g., the use of an acetylcholinesterase inhibitor in the dialysate) which may impede our ability to produce decisive  answers to the question of whether cortical ACh efflux is modulated in an area-specific manner, reflecting selective demands on, for example, motor versus sensory processing.

However, as we presently hypothesize that cortical ACh acts globally to gate cortical information processing, it is important to postulate that functional specificity arises on the basis of the interactions between cortical ACh efflux and other, converging input (from thalamus or other cortical areas; see Sarter & Bruno 1997). It is also important to keep in mind that, at higher levels of processing, evidence for a neuronal mediation of a specific stimulus condition or response may no longer be found. It may be the case that cortical ACh contributes to the general manifestation of "states of readiness for cognitive functioning" and to the allocation of processing resources (e.g., Turchi et al. 1997) and thus, the functions of ACh in "the real brain" (Rasmusson) is not optimally determined by searching for stimulus- or response-related modulation of processing. Obviously, if cortical ACh has such global yet crucial functions, pathological increases and decreases in the activity of cortical ACh will have major, escalating consequences for cognition (see our upcoming paper in TINS 1999, 22, 67-74).

We hope that these brief answers will help a bit in addressing some of these clearly crucial issues of any theory on the cognitive/behavioral functions of cortical ACh.