MDNews - Long Island

T HE MAPPING INITIATIVE — known as the Mouse Connectome Project (MCP) — recently achieved an important and unprecedented milestone: the fi rst charting of the mam- malian cerebral cortex. Results of the cortex mapping appeared in February in the journal Cell. "The mouse cerebral cortex is comprised of approximately 50 independent regions," says Houri Hintiryan, PhD, Assistant Professor of Research at the USC Institute for Neuroimaging and Informatics and a co-lead author of the study. "For decades, numerous studies have examined the connectivity of those individual cortical areas. For the most part, our connectivity data agree with those previous fi ndings. Although connectivity matrices of the cortex have also been assembled in other species, such as the cat and the monkey, none have previously shown how select groups of cortical areas are more interconnected than others to form distinct subnetworks with unique connectivity interactions." Previous cortical connectivity matrices were constructed piecemeal from data collected using a variety of methods in a multitude of small studies. Those fac- tors — combined with the limited space for publication of connection and injection site images in scientifi c journals — hampered comparison and analysis by the scientifi c community. MCP researchers have chosen to trace all of the pathways of the mouse brain and analyze the data in a standardized way. Investigators worldwide can view the data, including a cortical map, on the MCP website, http://mouseconnectome.org. "Collecting and analyzing all of the data systematically lends itself to detailed analysis that would not be possible oth- erwise," Dr. Hintiryan says. "That type of collection and analysis enabled us to identify eight subnetworks of the cortex that had gone undetected previously." Pathfi nders MCP researchers made 150 injections into a mouse subject's cortex; each injec- tion was made up of two circuit tracers that delineated four pathways using different- colored fl uorescent dyes. The methodology uncovered 600 unique cortical pathways. The researchers created a cortical connectivity map by incorporating 240 of the pathways into a conventional mouse brain atlas. "Analysis of the 600 cortical pathways showed certain cortical areas are more strongly interconnected at the cortical level than others," says Hong-Wei Dong, MD, PhD, Associate Professor of Neurology at the USC Institute for Neuroimaging and Informatics and senior author of the study. "That is to say, a group of cortical areas displayed a high level of cortical connectivity that organized them into eight distinct subnetworks." The subnetworks are: + Lateral subnetworks — One subnet- work along the edge of the brain may RESEARCHERS AT THE UNIVERSITY OF SOUTHERN CALIFORNIA ARE PAINSTAKINGLY MAPPING THE MOUSE BRAIN, A PROJECT WITH SIGNIFICANT IMPLICATIONS FOR UNDERSTANDING HOW STRUCTURES IN THE HUMAN BRAIN COMMUNICATE AND HOW DISRUPTIONS IN THEIR INTERACTIONS MAY AFFECT THE DEVELOPMENT OF NEUROLOGICAL DISEASES SUCH AS ALZHEIMER'S. be responsible for sensations such as hunger and pain, while the other could be a crossroads for information from every corner of the cortex. + Medial subnetworks — These two subnetworks occupy a central area in the cortex. Researchers postulated that the subnetworks may consolidate visual, auditory and spatial information. + Somatic sensorimotor subnetworks — Each of these four subnetworks controls a different part of the body, including torso and hind limbs, front limbs, facial muscles, and whiskers. Two other newly identified regions displayed high degrees of interaction with most of the cortex, indicating they might be critical areas for sending and receiving information. "What excited us most was that although the cortex is comprised of many individual regions that all appear to be connected, it actually displayed a very logical organiza- tion that grouped selected cortical regions with one another into these subnetworks," Dr. Dong says. "The functional assignments of these subnetworks need to be investigated further with appropriate behavioral studies; however, existing behavior and physiological data on these cortical structures provide clues to their roles." Disconnection and Disease The similarities between the mouse brain and the human brain make the rodent an ideal subject for obtaining insights about the human brain that researchers might never be able to glean otherwise. "Although the human brain is much more complex than the rodent's, the two organs share many common organizational principles," Dr. Dong says. "Technical limitations and ethical issues may make it impossible to map the human brain in the same resolution and comprehensiveness as what we can achieve with the mouse brain." MCP researchers' efforts to understand the order of brain connections may be the fi rst step toward developing a clearer picture of what happens when those connections are interrupted or function improperly. " M a ny p s y c ho p a t holo g ic a l a nd neurological diseases are now being identifi ed as pathologies of connections," Dr. Hintiryan says. "Brain regions don't work independently to control a behavior — their interactions and connections with other brain structures result in a desired behavioral output. As such, in a diseased state, it's the connections among the structures that are affected. The fi rst step in identifying these diseased connections is to gain a solid understanding of how these networks are inherently organized in healthy brains. Subsequently, we can examine aberrant connections within these networks in a variety of disorders. We want to avoid going beyond our data, but we feel the literature provides some strong evidence for cortical connection pathologies in attention defi cit hyperactivity disorder, schizophrenia and Alzheimer's disease." A driving force behind the MCP is the desire to give clinicians more options to treat those conditions. "Our group is seeking an opportunity to map the neuronal connectivity in different mouse models of neurological/neuropsy- chiatric diseases using our well-developed connectomic approach," Dr. Dong says. "That will provide more direct evidence for understanding the etiology of the 'discon- nection syndromes' and provide valuable reference for exploring novel treatments." ■ Of Mice and Men: Cracking the Mammalian Cerebral Cortex's Organizational Code By Thomas Crocker CORE CORE SPECIAL CLINICAL SECTION: NEUROSCIENCES M D N E W S . CO M ■ MD NEWS Long Island | 1 9

• Cover