The Dopaminergic Projection System, Basal Forebrain Macrosystems, and Conditioned Stimuli

Abstract

This review begins with a description of some problems that in recent years have beset an influential circuit model of fear-conditioning and goes on to look at neuroanatomy that might subserve conditioning viewed in a broader perspective, including not only fear, but also appetitive, conditioning. The paper then focuses on basal forebrain functional-anatomical systems, or macrosystems, as they have come to be called, which Lennart Heimer and colleagues described beginning in the 1970's. 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.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 PTSD 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's 2 model of this phenomenon, neuroplasticity reflecting the attachment of "significance" to a neutral stimulus, i.e., heralding the transformation of neutral to conditioned stimulus (CS), occurs in the amygdala, specifically its lateral nucleus (LA). According to LeDoux's model, 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, [1] sensory inputs bearing information about the aversive and neutral (to be conditioned) stimuli converge in LA 5 , and [2] an increase in the efficacy of CS-related synapses corresponds to conditioning [6][7][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 might serve as a relay interposed between LA and CeAm, the CeAl to CeAm projection is nearly exclusively inhibitiory (GABAergic) and thus would inhibit rather than activate outputs to brainstem. The model was accordingly adjusted to emphasize instead a projection from LA to amygda...

Inputs to the midbrain dopaminergic complex in the rat, with emphasis on extended amygdala‐recipient sectors

“…This interconnectivity of EAc structures with the RRF-PAGvl supports the conclusion that the RRF and PAGvl together represent a sector of the midbrain dopaminergic complex serving prominently as a node for outputs from EAc. These results complement earlier published findings by Hasue and Shammah-Lagnado (2004) indicating that projections originating in the PAGvl, including the dorsal raphe nucleus embedded within it, and the RRF, contain the majority of tyrosine hydroxylase-immunoreactive neurons providing innervation to the EA (see also Table in Zahm and Trimble, 2008). …”

Fos After Single and Repeated Self-Administration of Cocaine and Saline in the Rat: Emphasis on the Basal Forebrain and Recalibration of Expression

“…In view of this effect of repeated saline self-administration, increased Fos expression observed in SAC rats in most extended amygdala structures on day 6 as compared to day 1 might be due as much to the act of self-administering (as in saline self-administration) as to the effects of cocaine. Insofar as extended amygdala and lateral septum are implicated not only in neural responses to fear and anxiety (LeDoux et al, 1988; LeDoux, 1992; Duncan et al, 1996; Petrovic and Swanson, 1997; Davis and Shi, 1999; Sheehan et al, 2004; Phelps and LeDoux, 2005; Zahm and Trimble, 2008), but also arousal (Asmus and Newman 1994; Sheehan et al, 2004; Deurveilher et al, 2006; Valdés et al, 2006; Schlitz et al, 2007), increased Fos expression in the extended amygdala on day 6 may reflect arousal or anxiety that accompanies repeated self-administration.…”

Transcranial Sonography Findings in Depression in Association With Psychiatric and Neurologic Diseases: A Review

“…Beyond the context of movement disorders, an increased prevalence of SN hyperechogenicity has been found also in depressive disorders, possibly indicating an alteration, and malfunction of the mesencephalic dopaminergic system arising in the SN and the adjacent ventral tegmentum . The mesotelencephalic dopaminergic projection system connects to wide areas of the forebrain, including the striatum, the limbic system, and parts of the cerebral cortex . Mesolimbic dopaminergic projections are reported to be involved in a number of affect‐related functions, such as motivation, reward prediction, novelty detection, and learning .…”

“…20 The mesotelencephalic dopaminergic projection system connects to wide areas of the forebrain, including the striatum, the limbic system, and parts of the cerebral cortex. 21 Mesolimbic dopaminergic projections are reported to be involved in a number of affect-related functions, such as motivation, reward prediction, novelty detection, and learning. [22][23][24][25] The exact histopathologic correlate of SN hyperechogenicity still remains unclear, especially as it does not regularly correspond to iron-sensitive MRI findings.…”