CNS Spectr. 2008;13(1):32-34,37-40

Faculty Affiliations and Disclosures

Dr. Zahm is a professor in the Department of Pharmacological and Physiological Science at Saint Louis University School of Medicine in St. Louis, Missouri. Dr. Trimble is emeritus professor at the Institute of Neurology, Queen Square in London, United Kingdom, and the field editor of the journal.

Disclosures: Drs. Trimble and Zahm do not have an affiliation with or financial interest in any organization that might pose a conflict of interest.

Acknowledgment: The author is indebted to Beth DeGarmo, BS, for outstanding technical assistance.

Funding/Support: This work was supported by United States Public Health Service grants MH-70624, DA-15207, and NS-23805.

Submitted for publication: November 29, 2007; Accepted for publication: December 7, 2007.

Please direct all correspondence to: Daniel S. Zahm, PhD, Saint Louis University School of Medicine, Department of Pharmacological and Physiological Science, 1402 S. Grand Blvd, St. Louis, MO 63104; Tel: 314-977-8003, Fax: 314-977-6411; E-mail: zahmds@slu.edu.

Introduction

One of the most important neurobiological discoveries of all time was that of Olds and Milner in 1953, when they described the so-called “pleasure” circuits of the brain. Neuroscience had concerned itself mainly with cerebral events that underpinned cognition.Neurology was largely interested in “negative” symptoms, mainly what a neurological lesion took away. However, interest in the underlying neuroanatomy of motivation was largely ignored. The significance of unraveling the neuroanatomy of the basal forebrain for an understanding of “what makes you tick” comes to light in this contribution from Daniel S. Zahm, PhD, who introduces us to important neuroanatomical concepts that have recently evolved. In particular, he discusses basal forebrain functional-anatomical systems, referred to as macrosystems, which underlie so much of animal and human social behaviors, and the relevance of neurotransmitters, such as dopamine, for driving these behaviors.

Abstract

This review begins with a description of some problems that recently have beset an influential circuit model of fear conditioning and goes on to look at neuroanatomy that may subserve conditioning viewed in a broader perspective, including not only fear but also appetitive conditioning. The column will then focus on basal forebrain functional-anatomical systems, or macrosystems, as they have come to be called. Yet, more specific attention is then given to the relationships of the dorsal and  ventral striatopallidal systems and extended amygdala with the dopaminergic mesotelencephalic  projection systems, culminating with the hypothesis that all macrosystems contribute to behavioral conditioning.

Re-Tooling Fear Conditioning

There is tremendous current interest in the neurobiological mechanisms underlying conditioned fear stemming in large part from an increasing prevalence in American culture of anxiety and panic disorders, not to mention posttraumatic stress disorder.¹ By 2000, the relevant brain circuitry had seemed to be satisfactorily described,² but a number of serious caveats had been voiced the preceding year,³ and an unraveling process accelerated thereafter. Indeed, current theory on the neural substrates of fear conditioning has entered into a state of reassessment.⁴

The essential elements of fear conditioning are described by the observation that pairing neutral and fear-arousing stimuli causes the neutral one to gain meaning such that it can then drive an organism’s voluntary and involuntary actions. Thus, behaviorally, rats exposed to a brief tone followed immediately by a footshock will soon, frequently after a single trial, come to “freeze” upon hearing the tone. In LeDoux’s² model of this phenomenon, neuroplasticity reflecting the attachment of “significance” to a neutral stimulus (ie, heralding the transformation of neutral to conditioned stimulus [CS]) occurs in the amygdala, specifically its lateral nucleus (LA). According to LeDoux’s model,² the LA projects to another part of the amygdala, the central nucleus (CeA), which, in turn sends out divergent descending projections to somatic and autonomic motor effectors in the brainstem, eliciting behavioral freezing and accompanying autonomic responses. Consistent with the model, sensory inputs bearing information about the aversive and neutral (to be conditioned) stimuli converge in the LA5 and an increase in the efficacy of CS-related synapses corresponds to conditioning.^6-8 But, soon it was realized that the CeA consists of two parts: a medial division (CeAm), from which most of its descending projections arise and to which LA does not project, and a lateral one (CeAl), to which it does. While CeAl projects to CeAm and thus may serve as a relay interposed between the LA and CeAm, the CeAl to CeAm projection is nearly exclusively inhibitory (γ-aminobutyric acid-ergic [GABAergic]) and thus would inhibit rather than activate outputs to brainstem. The model was accordingly adjusted to emphasize instead a projection from the LA to amygdaloid “intercalated” nuclei,⁹ which are located between CeAm and CeAl and project to CeAm. This also is a GABAergic projection, however, making it difficult to conceive how this solves the problem, but because intercalated nuclei comprise several interconnected cell masses, it was reasoned that activation of one would inhibit its neighbor, which, in turn, would disinhibit the CeAm.¹⁰ This seems a possible but precarious foundation upon which to build such a biologically important function as fear conditioning, and, in any event, more issues came to plague the model.¹¹ Despite this accumulation of complications, the status of the amygdala as a major player in stimulus-consequence associations^12-15 seems not to be in jeaopardy,^4,16 although the underlying brain circuitry and physiological mechanisms seem to require further investigation.

Basal Forebrain Macrosystems

In considering this dilemma, it is important to remember that conditioning occurs not only in response to fear arousing and aversive stimuli but also to appetitive cues, as in, for example, conditioned place preference^17,18 and postural orienting directed to a CS,^19,20 and not only in the amygdala. Indeed, appetitive Pavlovian conditioned responses are abolished by lesions in the accumbens territory of the ventral striaum,¹⁷ which turns out to also contribute to specific forms of aversive conditioning.^21-24 Lesions of the CeA not only abolish aversive conditioning, as in freezing to a CS, as aforementioned, but also disrupt orienting to appetitive conditioned cues.^16,25 Thus, both structures support Pavlovian responses to fear arousing and appetitive stimuli, although each may “specialize” in one or the other. This suggests that both structures possess a general capacity to recognize stimulus “significance” and a more specialized capacity to assess the associated adaptive implications in order that a proper Pavlovian response will be mounted. Insofar as function follows structure, it seems reasonable to expect that the neuroanatomical organizations of the CeA and accumbens should also exhibit similarities and differences, and that these may provide some additional insight into the neural mechanisms that underlie conditioning.

This expectation is fulfilled by the concept of basal forebrain functional-anatomical systems or macrosystems, as they have come to be called.^26,27 Among these are the dorsal striatopallidal system (the basal ganglia, as classically described), ventral striatopallidal system (which, relevant to this discussion, includes the accumbens^28,29) and extended amygdala (which includes the CeA³⁰). Structural similarities shared by different macrosystems are reflected in a basic “framework,” essentially that of the basal ganglia,³⁰ in which massive projections from the cortical mantle or cortical-like structures,^31-33 a category that includes the LA, terminate densely in subcortical “input” structures consisting predominantly of medium-sized, densely spiny inhibitory (ie, GABAergic) neurons. Macrosystem input structures, including the CeA and accumbens, also receive massive inputs from the brainstem reticular formation via the midline/intralaminar thalamic nuclei and brainstem monoaminergic cell groups, especially dopaminergic. Medium spiny neurons, in turn, may project out of the macrosystem, as outputs, or massively to structures regarded as part of the macrosystem “intrinsic” circuitry constituting somewhat larger sparsely spined, GABAergic “pallidal”-like neurons with long radiating aspiny dendrites, such as found in the globus pallidus, ventral pallidum, and CeAm. Pallidal-like neurons may also project intrinsically or give rise to outputs. Macrosystem outputs diverge into re-entrant pathways to the forebrain, including cortex, via synaptic relays in the thalamus, forebrain, and brainstem and descending pathways to somatic and autonomic motor effectors, via relays in the hypothalamus, mesopontine tegmentum and caudal brainstem. Accompanying the host of basic similarities shared by macrosystems are a variety of features that distinguish them, such as the richness and extent of medium spiny neuronal intrinsic axonal arbors, the numbers and transmitter phenotypes of associated large interneurons and the quantity and indentities of neuropeptides, neuropeptide and transmitter receptors, and intracellular signaling cascades utilized.^30,34-36

Dopaminergic Innervation of Macrosystems

Early pioneering studies^37-41 revealed with astounding clarity that catecholaminergic and indoleaminergic cell groups embedded in the brainstem provide ascending and descending projections to virtually all parts of the brain and, particularly abundantly, to the basal ganglia and other basal forebrain structures. By distinguishing different fluorescent hues, these investigators discriminated norepinephrine and dopamine (which emit at similar wavelengths and were designated as “A” cell groups and projections) from serotonin (B groups) and epinephrine (C groups). Among the catecholamine-fluorescing cell groups subsequently identified as dopaminergic,⁴² the A8, A9 and A10 groups, occupying, respectively, the midbrain retrorubral field, substantia nigra compacta (SNc) and ventral tegmental area (VTA), are related by connections most strongly to the basal forebrain macrosystems. Although individually designated, A8, A9, and A10 actually comprise a single continuous constellation of dopaminergic neurons (Figures 1A–1F), approximating the form of an ellipsoid encircling the medial lemniscus with A10 (occupying the VTA) lodged in the ventromedial tegmentum and A8 (occupying the retrorubral field) and A9 (occupying the SNc), respectively, extending lateralward above and below the medial lemniscus to meet again in the ventrolateral tegmentum. In addition, an appendage of A8 arches caudomedialward toward the ventrolateral periaqueductal gray (Figure 1F). Where confluent (eg, * in Figure 1A and ** in Figure 1B), neurons in A8 are indistinguishable from those in A9 or A10, as are those in A9 from those in A10. Nonetheless, A8, A9, and A10 are structurally and functionally differentiated, as is reflected in the relatively distinct, albeit overlapping, topographies of their ascending projections^43-50 to be discussed later. Hökfelt and colleagues⁵¹ designated some additional dopaminergic districts, of which only one will be mentioned here, A10dc (dc—dorsal, caudal) is located in the mesopontine periaqueductal gray (PAG) in the vicinity of the dorsal raphe nucleus (Figures 1F and 2B).

A9 (the SNc) gives rise to the mesostriatal projection, which, essentially, provides dense dopaminergic innervation to the caudate nucleus and putamen (ie, the “input” nuclei of the basal ganglia). The caudate-putamen, which also receives massive input from isocortex (neocortex), is involved in the initiation and control of voluntary movements, development, and maintenance of motor habits, and possibly the structuring of some cognitive processes.⁵² In turn, the caudate-putamen and other basal ganglia structures, including the globus pallidus and substantia nigra project prominently to A9, which also receives ascending afferents from a number of structures in the brainstem. Mesolimbic projections from A10 (in the VTA) provide a dense dopaminergic innervation to ventral striatopallidum and, to a lesser extent, the extended amygdala (CeA, bed nucleus of stria terminalis and associated structures) as well as to a number of other sites in the basal forebrain, such as the septum and preoptic region. All of these structures project back to A10 directly, but this forms but part of the A10 afferent system, which comprises a nearly continuous and extensively interconnected formation of structures extending from the prefrontal cortex to the caudal brainstem.^53-56 Mesolimbic dopaminergic projections are reported to be involved in a broad range of functions, including locomotor activation,⁵⁷ reward,⁵⁸ motivation,⁵⁹ novelty detection,⁶⁰ reward prediction and error detection,⁶¹ and memory and learning.⁶² Moreover, A10 and its projections, particularly to the accumbens, were identified early on as the primary sites of attack of psychostimulant and opiate drugs of abuse, which were said to “hijack” the reward system. The A10 dopamine-accumbens axis soon became regarded as the target most subject to maladaptative neurochemical, molecular, and electrophysiological re-organizations in response to chronic and acute administration of such drugs.^63,64

In contrast, A8 (the retrorubral field) and its projection system and neural connections by comparison have been relatively neglected, having not even been considered in one classic description of the ventral mesencephalic efferents.⁶⁵ Nor did Lindvall and Björkland⁴⁶ or Loughlin and Fallon^47,48 have much to say about A8 in their respective chapters on central dopamine-containing neuronal systems, and Fallon⁵⁰ intentionally omitted consideration of A8 in deference to a brief report on it in the same congress.⁴⁹ As it turns out, just as A9 is most closely associated with neostriatum and the somatomotor apparatus, and A10 with the ventral striatopallidum,³⁶ A8 seems to be closely related to extended amygdala, which, as noted earlier, a substantial literature ties closely to behaviors driven by fear and anxiety.^66-68 Deutch and colleagues⁴⁹ sketched out connections of A8 with structures that would, in the same year, be defined as comprising the central division of the extended amygdala³⁰ and subsequent tract-tracing studies have born out this connectional relationship. Thus, A8 is densely innervated by the central nucleus of the amygdala^69,70 and bed nucleus of stria terminalis.^36,71 Interestingly, fibers descending from extended amygdaloid structures mainly pass through the VTA (A10) with minimal functional relationship (few axonal varicosities, regarded as sites of synaptic potency) before turning lateralward toward A8 and the lateral part of A9 (Figures 1A–1F and 2A), where many terminal axonal branches and axonal varicosities are observed. This varicosity-rich descending projection of the extended amygdala then continues beyond A8 to enter the periaqueductal gray, where it forms another dense plexus of varicosity-laden terminations among the putatively dopaminergic neurons comprising Hökfelt and colleagues’⁵¹ A10dc (Figures 1F and 2B). It has recently been shown that A10dc, which may utilize levodopa as a neurotransmitter in place of dopamine,⁷² represents that part of the A8–A10 complex that projects most robustly to the central division of the extended amgydala,⁷³ followed in decreasing order by A10 proper, A8, and A9 (Table). Thus, it may make sense to group A10dc neurons with A8, in view of their rich connectional relationship with the extended amygdala.

Conclusion

To summarize, fear conditioning is inadequately addressed by a circuit model proposed by LeDoux.² Conditioned stimuli reflecting fear-arousing and appetitive associations, are best subserved by the amygdala and accumbens, respectively, although the amygdala can modulate the formation of certain forms appetitive, as can the accumbens the formation of certain forms of aversive, associations. In view of this evidence, one may hypothesize that the capacity to recognize that a stimulus is significant, a more general aspect of Pavlovian conditioning, is reflected in neuroanatomical organization common to macrosystems, whereas synthesizing an appropriate response to specific stimulus modality (ie, fear arousing or appetitive) is reflected in their unique neuroanatomical features. Put more succinctly, the capacity of brain to form neural associations reflecting the interrelationships of various internal and external stimuli is hypothesized to be a property of all basal forebrain macrosystems and to involve their intrinsic and extrinsic connections.

It has been shown herein that shared and unique features also characterize the dopaminergic connections of macrosystems. Consistent with the striking reciprocity of connections between the SNc (A9) and caudate-putamen, VTA (A10) and accumbens, and A8/A10dc and extended amygdala, lesions and perturbations of dopaminergic innervations in the extended amygdala and accumbens do disrupt fear and appetitive conditioning, respectively,^74-79 and opposing modulations of the activity of dopaminergic neurons have been correlated with the presentation and omission of appetitive stimuli.⁶¹ While the precise role played by dopaminergic mechanisms within the macrosystems in the formation and expression of associations underlying conditioning remains to be determined, it seems likely that such associations are an important element in most of the functions that have been attributed to dopamine, such as locomotor activation, reward, motivation, novelty detection, reward prediction, error detection and memory and learning. The likelihood that dopaminergic actions on association formation play out in several different basal forebrain macrosystems, including the dorsal and ventral striatopallidum, extended amygdala, and the septal-preoptic system,^30,33,36,80 all acting somewhat differently on the same and different sets of neural associations, suggests that the use of dopaminergic drugs, whether therapeutic or illicit, may have wide-ranging behavioral effects.

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