In life, actions necessary to redress an organism's wants or needs are always accompanied by some level of threat to its well-being, requiring that choice mechanisms involve a capacity to weigh threat against potential gain. One working model of brain systems that might subserve such mechanisms includes the participation of basal forebrain functional-anatomical macrosystems, such as ventral striatopallidum, extended amygdala and septal-preoptic system. Much literature indicates that basal forebrain macrosystems are concerned with the formation of neural associations reflecting potentially rewarding and threatening aspects of internal and external stimuli. While the various macrosystems have their own domains of termination in the basal forebrain, subsets of outputs from all of them converge in the lateral preoptic area (LPO). LPO outputs, in turn, are aimed mainly at structures that directly control dopaminergic neuronal activity, including the lateral habenula (LHb), newly discovered rostromedial tegmental nucleus (RMTg) and the pedunculopontine tegmental nucleus and associated midbrain extrapyramidal area (PPTg/MEA). During the preceding funding cycle we observed that activation of the LPO, but not adjacent basal forebrain sites, such as the ventral pallidum, extended amygdala, sublenticular substantia innominata, or the diagonal band nuclei, stimulates ambulatory locomotion up to 10-fold over baseline. This robust locomotion was attenuated but not abolished by systemic injections of the dopamine receptor antagonist haloperidol, suggesting a significant independence of the response from dopamine neurotransmission. In contrast, locomotion elicited by injection of methamphetamine (1 mg/kg, s.c.) was blocked by an LPO infusion of the GABA A agonist muscimol. Insofar as locomotor activation is viewed as a behavioral expression of a sense of impending consummation from which intended motor acts may be launched, the specificity and sensitivity with which the LPO elicits locomotor activation combined with the convergence there of outputs from reward- and threat-sensitive macrosystems suggests that the LPO is a critical site where macrosystems influence behavior. In order to further pursue these ideas, we propose to provide [1] a detailed experimental chemical-neuroanatomical analysis of the pathways involving the LHb, RMTg and PPTg/ MEA by which the LPO influences the mesolimbic dopamine system and [2] functional analysis of LPO regulation of locomotion, threat response and conditioned place preference in the presence and absence of dopamine neurotransmission. Impulsive, maladaptive decision-making is a major societal concern that accompanies anxiety, depression, panic, compulsion, and attention disorders and underlies chronic joblessness, dysfunctional interpersonal relationships, ruinous child-rearing and addictions. Addiction, if regarded as behavior compulsively repeated in the certain knowledge of its self-destructiveness, is bad decision-making by definition. The proposed studies will reveal non-dopaminergic and dopaminergic mechanisms that modulate LPO-elicited locomotor activation, which we propose contributes to the neural processes that underlie impulsive decision-making.

Public Health Relevance

Impulsive, maladaptive decision-making accompanies anxiety, depression, panic, compulsion, and attention disorders and underlies chronic joblessness, dysfunctional interpersonal relationships, ruinous child-rearing and addictions. Addiction, if regarded as behavior compulsively repeated in the certain knowledge of its self- destructiveness, is bad decision-making by definition. The proposed studies will reveal mechanisms by which activity is elicited in a basal forebrain structure called the lateral preoptic area and how this in turn affects neural processes that underlie impulsive decision-making.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS023805-24A1
Application #
8576650
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Chen, Daofen
Project Start
1986-09-01
Project End
2018-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
24
Fiscal Year
2013
Total Cost
$328,125
Indirect Cost
$109,375
Name
Saint Louis University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Lavezzi, Heather N; Parsley, Kenneth P; Zahm, Daniel S (2015) Modulation of locomotor activation by the rostromedial tegmental nucleus. Neuropsychopharmacology 40:676-87
Zahm, Daniel S; Schwartz, Zachary M; Lavezzi, Heather N et al. (2014) Comparison of the locomotor-activating effects of bicuculline infusions into the preoptic area and ventral pallidum. Brain Struct Funct 219:511-26
Yetnikoff, L; Lavezzi, H N; Reichard, R A et al. (2014) An update on the connections of the ventral mesencephalic dopaminergic complex. Neuroscience 282C:23-48
Yetnikoff, Leora; Reichard, Rhett A; Schwartz, Zachary M et al. (2014) Protracted maturation of forebrain afferent connections of the ventral tegmental area in the rat. J Comp Neurol 522:1031-47
Uchoa, Ernane Torres; Zahm, Daniel S; de Carvalho Borges, Beatriz et al. (2013) Oxytocin projections to the nucleus of the solitary tract contribute to the increased meal-related satiety responses in primary adrenal insufficiency. Exp Physiol 98:1495-504
Zahm, Daniel S; Parsley, Kenneth P; Schwartz, Zachary M et al. (2013) On lateral septum-like characteristics of outputs from the accumbal hedonic "hotspot" of Pecina and Berridge with commentary on the transitional nature of basal forebrain "boundaries". J Comp Neurol 521:50-68
St Onge, Jennifer R; Stopper, Colin M; Zahm, Daniel S et al. (2012) Separate prefrontal-subcortical circuits mediate different components of risk-based decision making. J Neurosci 32:2886-99
Lavezzi, Heather N; Zahm, Daniel S (2011) The mesopontine rostromedial tegmental nucleus: an integrative modulator of the reward system. Basal Ganglia 1:191-200
Zahm, Daniel S; Cheng, Anita Y; Lee, Tristan J et al. (2011) Inputs to the midbrain dopaminergic complex in the rat, with emphasis on extended amygdala-recipient sectors. J Comp Neurol 519:3159-88
Zahm, Daniel S; Becker, Mary L; Freiman, Alexander J et al. (2010) Fos after single and repeated self-administration of cocaine and saline in the rat: emphasis on the Basal forebrain and recalibration of expression. Neuropsychopharmacology 35:445-63

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