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Home , Neurophysiology, Psychopharmacology

FIELD EDITOR EDITORIAL

The Future of in

Information processing in the occurs primarily by technique for which Sakmann and Neher won the No- electrical impulses in that release neurotrans- bel Prize, is an extremely powerful method to analyze mitters and influence the electrical activity of other neu- neurophysiological function at the molecular level. Us- rons. This function is regulated by a variety of factors, ing this methodology, one can easily test the effects of and is the primary target of aimed at treating minute manipulations of the molecular structure of re- mental dysfunctions. Thus, the study of electrical activ- ceptors and their associated channels, as well as the in- ity in neurons (neurophysiology) is at the heart of how dividual subunits of G proteins and second messenger the brain processes information and how drugs influence systems. One can determine exactly at what amino ac- mental functioning, and is central to neuropsychophar- ids in the protein of the channel molecule or subunit an macology. antagonist or acts, or at what point protein phos- The importance of neurophysiology in neuropsy- phorylation modulates function. Such com- chopharmacology is confirmed with the reorganization bined molecular biology and neurophysiology allows of this Journal, and the creation of a separate field of for the first time a definitive connection between struc- neurophysiology for the review of submitted manu- ture and function at the molecular level. The upshot of scripts. In this editorial, I emphasize the importance of this for neuropsychopharmacology is that such an un- neurophysiology to neuropsychopharmacology now derstanding will allow (i) a more detailed understand- and in the future. Compared to the role that it plays, ing of the functional basis of genetically linked disor- and will play, in neuropsychopharmacology, neuro- ders of brain function, and (ii) the rational development has been under-represented in this journal. of more effective and selective pharmacological agents A major goal of mine is to publish greater numbers of and therapeutic drugs. For example, understanding outstanding neurophysiology articles in Neuropsycho- what part of the NMDA receptor-channel complex is af- . fected by alcohol could lead to the development of a There are several aspects of neurophysiology that drug to blunt alcohol antagonism of NMDA receptor stand out as having substantial promise for neuropsy- function, to be responsible for many aspects of chopharmacology in the future. These span the neuro- alcohol intoxication. It should also be noted that these physiology spectrum, from molecular neurophysiology neurophysiological methods are readily applicable to to behavioral and cognitive neurophysiology. As samples (e.g., slices or cultures from biopsies) pointed out below, integration among these fields is a so that functional data for single molecules (e.g., chan- growing, and increasingly powerful, aspect of neuro- nels) can be compared for tissue from normal and dis- physiology. eased .

MOLECULAR NEUROPHYSIOLOGY CELLULAR NEUROPHYSIOLOGY

This is an area that is developing rapidly, and has al- Although the neurophysiological analysis of single ready made substantial contributions to our field. Patch molecules is an important avenue for understanding clamp analysis of currents through single channels, a the molecular and genetic bases of mental disorders,

NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 5 © 1999 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(99)00013-5

510 Editorial NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 5

such findings must be integrated into a cellular-level stand how such activity influences other brain areas, analysis to understand how channel, receptor, and mes- and ultimately contribute to a psychological or behav- senger molecules influence information processing in ioral function. Many studies at this level that are impor- the . No single channel operates alone in tant for neuropsychopharmacology involve extracellu- determining the impulse activity of a ; instead, lar recording of impulse activity from neurons in a each neuron integrates thousands of synaptic inputs, particular brain area in response to drug administration and even greater numbers of ion channels, in determin- in anesthetized animals. Studies using local drug ad- ing cellular . The functional signifi- ministration are important for determining the site of cance of the ever advancing insights into diffusable in- drug effects where inputs that may be severed in the tracellular 2nd messenger molecules can be very slice remain intact. Studies using systemic drug admin- profitably studied by intracellular or whole- patch istration lack information about locus of action, but are clamp analysis in cultured neurons or brain slices. Cur- important nonetheless to determine how the drug af- rent and future work using such cellular neurophysiol- fects specific neurons when given in a clinically rele- ogy in slices and cultures from animals with specific ge- vant dose and manner. Investigations in brain slices of- netic manipulations of specific molecules (via, e.g., ten lose sight of the fact that neuronal properties can be transgenic or knockout techniques) will be critical to substantially altered in the process of obtaining the slice understand the importance of such manipulations for (truncation of dendrites, loss of synaptic inputs, loss of the function of specific brain neurons. These ap- circulating factors, etc.). Therefore, analyses of drug ac- proaches are also critical to drug development. For ex- tions using intracellular recordings in the intact animal ample, the design of neuroleptics that interfere with a is an important (more physiologically relevant) exten- particular subset of or receptors on sion of similar studies in brain slices that deserves more identified cortical neurons is now a feasible undertak- attention in the future. Recent advances in multichannel ing with slice or culture neurophysiology. electrode recording, as well as optical imaging methods Electrotonic coupling is an aspect of cellular neuro- for cortical as well as subcortical structures in the intact physiology that is not considered frequently in neuro- animal, offer exciting new approaches to study the ac- . This communication via gap junc- tivities of populations and networks of neurons in the tion channels formed by connexin proteins in neuronal intact animal. membranes is known to be common during develop- ment. It is believed that in the mature CNS electrotonic coupling exists in only a few specialized areas such as retina and inferior olive. However, increasing evidence BEHAVIORAL NEUROPHYSIOLOGY indicates that such coupling may be much more wide- spread than originally believed. Neurons appear to be This is the ultimate level of integration in neurophysiol- electrotonically coupled in the adult caudate and nu- ogy. These studies specify the behavioral significance of cleus accumbens, as well as in noradrenergic neurons of neurophysiological properties of single molecules, indi- the locus coeruleus and dopaminergic cells of the sub- vidual neurons, and circuits and networks of neurons. stantia nigra. Notably, this coupling is flexible, and can This level of analysis employs single neuron recording appear or vanish with changes in in- in animals, or slow-wave recording in , and is puts and 2nd messenger molecules. This raises the possi- critical for studying brain mechanisms of complex be- bility that electrotonic coupling may be targeted in a haviors and cognitive processes. While molecular and selective manner by drugs. The ability of electrotonic cellular experiments are important for understanding coupling to synchronize activity among neurons, and details of processes involved in mental dysfunction or the powerful effects of neuronal synchronization on in- drug responses, they are unable to integrate such re- formation processing in the brain, indicates that the sults to ultimately and completely explain cognitive func- pharmacology of electrotonic coupling is an important tions such as attention, , , or mem- area of investigation for neuropsychopharmacology in ory. An analogous relationship exists between physics the future. and chemistry: While the principles of physics are criti- cal to our understanding of chemistry, they are not suf- ficient to fully predict or understand the properties of chemical reactions. It is fundamentally necessary to con- SYSTEMS NEUROPHYSIOLOGY duct experiments in chemistry per se or, as is the case at hand, in behavioral neurophysiology. Just as the influences of individual molecules must be Although the behavioral functions of brain areas can integrated to understand their functional significance at also be examined with lesions, there are several prob- a cellular level, the operations of individual neurons lems inherent with many such approaches (plasticity, must be integrated into circuits and networks to under- recovery of function, etc.). Recordings in animals per-

NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 5 Editorial 511

forming a behavioral task allow a less invasive analysis tized animals, as anesthesia may have profound effects of the behavioral role of neurons. If the neurons in ques- on drug responses of neurons. One area that is only lit- tion are involved in a particular , then their ac- tle studied is the activity of individual brain neurons in tivity should vary with that behavior in a predictable animals self-administering drugs, or in other types of manner. More often than not, recordings detail much drug abuse studies. A particularly large gap exists in more about possible neural involvement in a specific this regard concerning the cognitive effects of abused behavioral or cognitive process than originally imag- drugs. Certainly involves important changes ined. This is important, as such are an im- in attention, , and other high-level cognitive portant source for hypotheses about the behavioral processes. These processes cannot be understood with functions of brain areas, which can then be elaborated molecular or cellular studies of the effects of addictive with computational modeling approaches, and tested drugs alone. Studies of the effects of addictive drugs on with manipulations of the neurons in question (de- target neurons in, e.g., behaving primates performing scribed below). cognitive tasks that tap into changes associated with Computational modeling has traditionally been ap- addiction, will provide exciting new views on brain plied to cellular analyses of neurophysiological func- substrates of addiction. tion using biologically realistic models. However, there A final point that is noteworthy here is that behav- is a great deal to be gained from the iterative interaction ioral neurophysiology is critical for a mechanistic under- between modeling and neurophysiology at the behav- standing of cognitive processes studied with functional ioral level as well. One approach that has great promise imaging techniques. A danger in imaging studies (e.g., for the future is the use of hybrid models, composed of PET or fMRI) is that scanned images of, e.g., increased a biologically realistic component to capture the neu- activity in area X during task Y may be interpreted to rons being recorded plus a more abstract connectionist mean that area X mediates a function presumably component to represent the behavior performed during tapped by task Y. This thinking resembles the recordings. Such models are a powerful means to of many years ago. Lost in this equation is the fact that make hypotheses about the behavioral functions of neu- area X transforms the signals it receives, before passing rons more specific and testable. them on elsewhere. These signals are transmitted and Microinjections into brain areas of behaving animals transformed at the cellular level, via electrical and neu- are an excellent alternative to lesions for testing hypoth- rochemical signaling. The real function of area X is not eses about the behavioral function of a brain area. This the global behavioral or mental process targeted by the approach can be combined with neurophysiology, so task, but rather the transformation of the signals fed that the activity of neurons can be monitored from an through X, and on to X’s targets. Thus, whereas scan- electrode adjacent to a cannula injecting, for example, ning denotes areas that may be involved in particular an inhibitory agent. This produces an immediate, tran- and processes, behavioral neurophysiology sient “lesion” that is not subject to the confounds of per- is required to elucidate the functions of those areas and manent lesions, and also gives a temporal index of the the underlying mechanisms. change in activity of the cells in question to correlate In addition to these neuronal analyses in behavioral with the behavior of the animal. If specific neurons dis- neurophysiology, new approaches in ERP and EEG re- charge in relation to the behavior, and manipulations of cordings have substantial promise. Investigators are learn- those neurons by local chemical means produce cogni- ing a great deal about the progression of signal process- tive or behavioral changes that are consistent with the ing, and the localization of such processing to specific recordings, strong evidence is obtained in favor of the brain areas, by the use of large numbers of scalp electrodes behavioral role for these neurons. Such local microinjec- in humans. Such studies offer a great deal of promise in tion/recording techniques in behaving animals can also conjuction with fMRI and other functional imaging. The be used to test the sites of action of drugs for specific be- spatial accuracy and resolution of imaging techniques havioral effects. complements the temporal resolution of ERP methods, Another area of substantial potential here is the use so that studies in intact humans can be performed with of multiple electrodes to simultaneously record activi- much substantial spatial and temporal resolution. ties of several individual neurons during behavioral ex- In conclusion, neurophysiology is critical for the fu- periments. Studies of this type are important as they ex- ture of neuropsychopharmacology. Neuropsychophar- tend the analysis of single neurons to networks of macology is dependent upon neurophysiology for neurons. It is, of course, networks of cells, not individ- mechanistic understanding of mental function and dys- ual neurons, which underlie complex behavior. function, and of drug actions in brain and behavior. In addition, very little work at the interface of neuro- This mechanistic knowledge is also important for the physiology and in has been done development of better pharmacologic tools. Given the in behaving animals. Clearly, it is important to investi- central importance of neurophysiology to neuropsy- gate the neurophysiology of drug actions in unanesthe- chopharmacology, I believe that neurophysiology is un-

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der-represented in this journal. As the new field editor manuscripts in these areas are encouraged to provide for neurophysiology, I hope to change this situation. the most current and important studies to our field. Neuropsychopharmacology is the logical vehicle for com- municating new insights in neurophysiology to basic Gary Aston-Jones, Ph.D. and clinical in this field. Neurophysiology ar- Department of ticles in all of the areas discussed above are of high rele- University of Pennsylvania School of vance to neuropsychopharmacology, and high quality Philadelphia, PA