Research reportCentral representation of the sympathetic nervous system in the cerebral cortex
Introduction
Psychological factors influence autonomic, neuroendocrine, and immune functions in complex ways that are not well understood, often exacerbating clinical conditions such as cardiac diseases or even possibly being a contributing factor in some diseases [42]. Even in healthy individuals, emotions trigger visceral responses [40] — raising the possibility that there is a common set of cortical-limbic circuits which affect autonomic functions. Although this is one of the oldest issues in neuroscience and can be traced back to the 19th century when Bochefontaine [2] demonstrated that electrical stimulation of the cerebral cortex produced visceral changes, a complete map of the cortical areas which influence sympathetic functions has not been obtained.
In the 125 years that have elapsed since this initial observation, there has been a continued interest in identifying the regions of the cerebral cortex that modulate autonomic functions in the hopes of understanding how higher-level brain mechanisms affect visceral functions, particularly in human diseases. For the most part, however, the technological approach used in experimental studies has remained the same, viz., electrical stimulation mapping studies [31], [47]. This technique has one major drawback and that is, it is nonspecific. For example, when a particular cortical area is electrically stimulated, the response may be caused by activation of one (or more) of the three following structures: (1) cortical neurons lying at the site of stimulation; (2) fibers-of-passage originating from other cortical regions which traverse the site of stimulation (i.e., cortico-cortical circuits); or (3) incoming axons originating from hypothalamocortical and/or brainstem-cortical neurons (e.g., parabrachial nucleus) that innervate the cortical area being stimulated, but since these neurons may also have axonal branches that link them to the central autonomic system, the response would be due to the combined effect of antidromic and anterograde axonal excitation. To circumvent this problem, chemical stimulation methods have been used [10], [50], but a full account of the cortical regions that affect sympathetic functions is still lacking.
Anatomical techniques have not been fruitful for defining the corticosympathetic regions because most cortical areas do not project directly to sympathetic preganglionic neurons, but are part of multineuronal circuits that have relays in the hypothalamus and/or brainstem. Hence, standard tract tracing methods are inadequate for deciphering these pathways. In contrast, however, the viral transneuronal labeling method is an ideal technique for this type of analysis [25] and has been used by us to map the central sympathetic system from the preoptic region to the spinal cord [19], [43], [49].
The purpose of the present study was to obtain a comprehensive map of the areas of the cerebral cortex which modulate the sympathetic nervous system. By studying the sympathetic outflows of the heart, gastrointestinal tract, and adrenal medulla independently, we report here that a common pattern of sympathetic representation is found in the medial prefrontal cortex, insular cortex, ventromedial temporal lobe, and ventral hippocampal region. These findings are discussed in terms of emotional–autonomic responses along with consideration of their potential role in certain psychosomatic disorders.
Section snippets
Methods
The Bartha strain of pseudorabies virus (PRV; 50 nl; titer=108 plaque forming units/ml) was injected into one of three different sympathetic targets (viz., adrenal gland, stellate ganglion, or celiac ganglion) of pentobarbital-anesthetized (50 mg/kg) Sprague-Dawley rats (male; 350–400 g; n=60; Simonsen Lab, Gilroy, CA, USA). These targets were chosen to provide information regarding a range of different functional systems. Prior to injecting PRV into any of the sympathetic targets, a
Results
A similar pattern of forebrain labeling was found in the three types of sympathetic experiments, although temporal and quantitative differences were observed. In the early stage (5 days post-injection for the stellate and adrenal gland experiments), transneuronal labeling was found in the paraventricular and lateral hypothalamic nuclei, preoptic region (medial preoptic nucleus and medial preoptic area), bed nucleus of the stria terminalis, substantia innominata, and central nucleus of the
Discussion
This study demonstrates that four cortical regions, viz., infralimbic, insular, ventromedial temporal, and ventral hippocampal areas, are linked by multisynaptic connections to the sympathetic outflows which regulate the adrenal medulla, heart, and gastrointestinal tract. While it has been known for some time that both the infralimbic and insular cortical regions influence autonomic functions, the observation that the medial temporal cortex and ventral hippocampus are part of the central
Conclusion
The data presented here fulfill the predictions made in 1887 by Jackson [18] that suggest the autonomic nervous system is modulated by the emotional-processing areas of the cerebral cortex. On the basis of human imaging studies, we now know that the medial prefrontal cortex, insular cortex, ventromedial temporal cortex, and ventral hippocampus are activated during emotional events [21], [24], [34]. As shown here, all of these regions are connected to the sympathetic nervous system. Assuming
Acknowledgements
Supported by NIH grant HL-25449. We thank W.A. Field, K.E. Krout, D.A. Leib, and X.V. Nguyen for their help.
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