Making the Right Connections

Abstract

Recent years have seen the application of increasingly powerful transgenic, optogenetic, and chemogenetic methodologies in rodents. Armed with these tools, many studies have shown how perturbations of specific subregions of the rodent frontal cortex can elicit circumscribed behavioral phenotypes that resemble key aspects of psychiatric disorders. For example, the rodent frontal cortex can be broadly divided into motor, medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC) divisions; the mPFC can be further subdivided into prelimbic (PL), infralimbic (IL), and cingulate (Cg) cortices, while the OFC comprises the medial orbital (MO) and ventral and lateral orbital (VOLO) cortices. Recent studies have specifically linked changes in MO and VOLO activity to the expression of repetitive grooming behavior, which may model aspects of obsessive-compulsive disorder ( 1 Ahmari S.E. Spellman T. Douglass N.L. Kheirbek M.A. Simpson H.B. Deisseroth K. et al. Repeated cortico-striatal stimulation generates persistent OCD-like behavior. Science. 2013; 340: 1234-1239 Crossref PubMed Scopus (325) Google Scholar , 2 Burguiere E. Monteiro P. Feng G. Graybiel A.M. Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. Science. 2013; 340: 1243-1246 Crossref PubMed Scopus (294) Google Scholar ), while many other studies have linked subregions of the mPFC to aspects of social behavior, cognitive flexibility, working memory, chronic pain, and anxiety. At the same time, a plethora of human brain imaging studies have implicated frontal cortical networks in a variety of neuropsychiatric disorders. Notably, the subcallosal cingulate gyrus—which includes Brodmann area 25 (a25), parts of area 24 (a24), and area 32 (a32)—has been a focus of attention since it was found that deep brain stimulation of this region can alleviate treatment-resistant depression in some patients ( 3 Hamani C. Mayberg H. Stone S. Laxton A. Haber S. Lozano A.M. The subcallosal cingulate gyrus in the context of major depression. Biol Psychiatry. 2011; 69: 301-308 Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar ). Taken together, these and numerous other studies across humans, nonhuman primates (NHPs), and rodents suggest that many psychiatric disorders may be reconceptualized as disorders of brain networks within which prefrontal or orbitofrontal regions represent key nodes. In this context, a central challenge is identifying homologies between cortical regions in humans and animal models, so that insights obtained via the use of cutting edge tools in animal models can be translated to those regions of the human brain that have been directly implicated in psychiatric disease. And while many modern neuroscientific tools can be most readily exploited in rodents, the rodent prefrontal and orbitofrontal cortices are vastly underdeveloped compared to their human counterparts. Therefore, NHPs represent a critical bridge that may facilitate the synthesis of findings across rodent and human studies. However, achieving this synthesis has been challenging. In particular, there are many possible ways to identify corresponding brain regions across species [e.g., based on cytoarchitectonic features and corticocortical connectivity ( 4 Ongur D. Price J.L. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000; 10: 206-219 Crossref PubMed Scopus (2048) Google Scholar ) or patterns of neuronal activity and behavioral functions ( 5 Seamans J.K. Lapish C.C. Durstewitz D. Comparing the prefrontal cortex of rats and primates: insights from electrophysiology. Neurotox Res. 2008; 14: 249-262 Crossref PubMed Scopus (167) Google Scholar )]. In addition, there is controversy about whether many regions of primate PFC have rodent analogs at all ( 6 Wise S.P. Forward frontal fields: phylogeny and fundamental function. Trends Neurosci. 2008; 31: 599-608 Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar ). Circuit-Based Corticostriatal Homologies Between Rat and PrimateBiological PsychiatryVol. 80Issue 7PreviewUnderstanding the neural mechanisms of psychiatric disorders requires the use of rodent models; however, frontal-striatal homologies between rodents and primates are unclear. In contrast, within the striatum, the shell of the nucleus accumbens, the hippocampal projection zone, and the amygdala projection zone (referred to as the striatal emotion processing network [EPN]) are conserved across species. We used the relationship between the EPN and projections from the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) to assess network similarities across rats and monkeys. Full-Text PDF