The Midbrain Dopaminergic System: Anatomy and Genetic Variation in Dopamine Neuron Number of Inbred Mouse Strains Laszlo Zaborszky 1,3 and Csaba Vadasz 2,3 The mesotelencephalic dopamine system is genetically variable and affects motor behavior, mo- tivation, and learning. Here we examine the genetic variation of mesencephalic DA neuron num- ber in a quasi-congenic RQI mouse strain and its background partner and in a recombinant in- bred strain with different levels of mesencephalic tyrosine hydroxylase activity (TH/MES). We used B6.Cb4i5-6/Vad, C57BL/6By, and CXBI, which are known to express high, intermedi- ate, and low levels of TH/MES, respectively. Unbiased stereological sampling with optical di- sector counting methods were employed to estimate the number of TH-positive neurons in the A8–A9–A10 cell groups. Morphometric studies on the mesencephalic dopamine cell groups in- dicated that male mice of the B6.Cb4i5-6/Vad strain were endowed with a significantly lower number of TH-positive cells than CXBI mice. In all strains studied, the right retrorubral field (A8 area) had a higher number of dopamine neurons compared to the left A8 area. The results suggest an inverse relationship between TH/MES and number of dopamine neurons in the A9–A10 cell groups and significant lateral asymmetry in the A8 cell group. A detailed anatom- ical atlas of the mesencephalic A8–A9–A10 dopaminergic cell groups in the mouse is also pre- sented to facilitate the assignment of TH-positive neurons to specific cell groups. KEY WORDS: Complex trait; QTL introgression; tyrosine hydroxylase; dopamine neuron; stereology; mesencephalon. Behavior Genetics, Vol. 31, No. 1, 2001 47 0001-8244/01/0100-0047$19.50/0 © 2001 Plenum Publishing Corporation (Hornykiewicz, 1979), attention-deficit hyperactivity disorder (Faraone and Biederman, 1998), substance abuse (Koob, 1999), and in the control of motor ac- tivity and learning (Beninger, 1983), attention (Ya- maguchi and Kobayashi, 1998), and other behaviors. Although it is well established that genetic factors con- tribute to variations at both the neural and the behav- ioral levels, it has been difficult to clarify the mecha- nisms by which these behaviors are modulated by a specific genetic change in the mesotelencephalic dopamine system. The integrated use of more refined genomic, neurobiological, and behavioral strategies is needed for the better understanding of these mecha- nisms. Toward this end, we conceptualized and ex- perimentally tested quasi-congenic recombinant QTL introgression (RQI) animal models for continuously distributed quantitative traits by the development of B6.C and B6.I replicate lines (Vadasz, 1990) and sets INTRODUCTION In the past several decades, it was hoped that genetic strain differences in neural phenotypes (e.g., in brain morphology or in neurotransmitter level) would ex- plain associated behavioral differences and that such a discovery would lead to the development of animal models for human pathological behavior. The mesote- lencephalic dopamine system has been implicated in several neuropsychiatric disorders, such as schizo- phrenia (Meltzer and Stahl, 1976), Parkinson’s disease 1 Center for Molecular and Behavioral Neuroscience, Rutgers Uni- versity, 197 University Avenue, Newark, New Jersey 07102. Fax: (973)353-1844. e-mail: zaborszk@axon.rutgers.edu. 2 Neurobehavioral Genetic Research Program, New York University Medical Center, The Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, New York 10962. Fax: (845)398-5531. e-mail: VADASZ@NKI.RFMH.ORG. 3 Correspondence may be addressed to either author.