《认知神经科学》课程教学资源（参考文献）[Goldman-Rakic, P. S.（1987）]Development of cortical circuitry and cognitive function

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Development of Cortical Circuitry and Cognitive Function Patricia S. Goldman-Rakic Yale Unit>ersity School of Medicine GOLDMAN-RAHC, PATMCIA S. Development of Cortical Circuitry and Cognitive Function. GHILD DEVEIJOPMENT, 1987,58,601-622. Recent fiinctionai and anatomical studies in nonhuman primates have elucidated the basic neural circuitry underlying delayed-respohse function in adult nonhuman primates. Thus circuitry includes connections of the principal sulcus with other areas of parietal association and limbic cortex and projections to the caudate nucleus, superior colliculus, and other premotor centers. Anatomical tracing in primate fetuses and in monkeys at various stages of postnatal development indicates tfiat these various classes of cortical connections begin to form by tiie second trimester of pregnancy. Electromicroscopic studies of the principal sulcus and odier areas of cerebral cortex show that the number and density of synapses in die cortex increase rapidly, reaching and maintaining higher tiian normal adult values between 2 and 4 montfis postnatally, before slowly declining over a period of years to stable adult levels. The capacity to perfonn delayedresponse and/or AB at short delays emerges around 4 months of age, coinciding with the end of the period of highest synaptic density in the principal suleus. These findings suggest that a critical mass of cortical synapses is important for die emergence of this cognitive function, and that fully mature capacity may depend upon the elimination of excess synapses that occurs during adolescence and young adulthood. Knowledge of the neural basis of nonnal cognitive development may prove useful both to social and educational purposes as well as to understanding developmental disorders of cognition. Research on the development of behavior has proceeded for decades without benefit of knowledge about the underlying neurological maturation that is correlated with and absolutely necessary for the emergence of increasingly complex functions with age. Historically, &e absence of hard facts about neurological development was due to many factors. First and foremost, the methods of neuroanatomy, neurophysiology, and neurochemistry were relatively primitive and concepts of developmental mechanisms were accordingly rather general. Developmental study by its nature requires the ability to quantify change, and, except for biochemical assays, until quite recently, genuine quantitative approaches were not feasible for measuring many parameters of neural maturation. A second impediment to developmental neurological studies was initially the lack of detailed knowledge about the structural and functional organization of the adult mammalian brain, but that circumstance no longer exists. A third and not insignificant fector undoubtedly was the antinativist climate and "empty organism" cult that permeated mainstream psychology for almost half a century, still felt in many prominent departments of psychology even today. The "empty organism" has long since been filled wilii intentionality and information-processing skills, but not necessarily with a central nervous system. Circumstances for a genuine neurobiological science of mammalian development have changed radically in the past 15 years. Mfgor technical advances have taken place in the fields of neuroanatomy, neurophysiology, and neurochemistry, and, moreover, the conceptual and technical boundaries between diese once strictly parochial disciplines have merged together into the truly multidisciplinary endeavor of neuroscience. These advances have allowed definition of the circuitry by which neural systems carry out specific functions, including discovery of the neurotransmitters, enzymes, and neuromoduIators that are at the heart of intercellular communication. Moreover, whereas studies of neural embryology were once associated largely with research in avian and amphibian species, the development of the technique of prenatal surgery has opened up the possibility for unprecedented experimental studies in mammals, including fetal primates (Raldc 6c Goldman-Rakic, 1982, 1985). Send request for reprints to Section of Neuroanatomy, C303 Sterling Hall of Medicine, Yale University School of Medicine, P.O. Box 3333 New Haven, CT 06510-8001. IChM Developmeat, 1987,58,601-622. O 1987 by the Society for R€ssearch in Ghild Development, Inc. All rights reserved. 000&O920/87/5803-0021*01.00]

602 Child Development The present article will review recent studies conducted in my laboratory that concern the biologica] development of the prefrontal cortex in rhesus monkeys. We have been particularly interested in prefironta! cortex because its preeminent role in cognitive functions makes it a part of the brain with special significance for human society and culture. Moreover, this is one of the few areas of association cortex that has been characterized sufficiently well anatomically, biochemically, and functionally in adult monkeys to provide an adequate basis for developmental comparison (for review, see Fuster, 1980, 1985; Goldman-Rakic, 1987; Stuss & Benson, 1986). One major goal of our studies has been to construct a neurology for particular cognitive functions and to determine die critical cellular events necessary for mature function to emerge. Knowledge of the normal sequence and mechanisms of neur^ maturation is necessary, in my opinion, for approaching many basic issues in cognitive and developmental psychology. It is also fundamental for interpreting the pathological processes that occur both in severe developmental disorders such as mental retardation, childhood schizophrenia, and autism as well as in milder conditions like dyslexia and minimal brain dysfunction. SynopolB of Prefirontal Function in Adult Primates Delayed responses: Regulation of behavior by representational knowledge.—In monkeys, a specific subregion of the prefrontal cortex, that surrounding the principal sulcus (shown in Fig. 2A and to be described further in a later section), mediates performance on delayed-response tasks (e.g., Goldman et al., 1971; Goldman & Hosvold, 1970; GoldmanRakic, in press; Harlow, Davis, Settiage, & Meyer, 1952; Jacobsen, 1936). Humans with bilateral prefrontal lesions are also severely impaired on these tasks (Freedman & OscarBerman, 19^). Aldiough the dependence of delayed-response performance on prefrontal cortex is very well established, it's functional signiiicance is not usually fully appreciated (but see Fuster, 1980, 1985; GoIdman-Raklc, in press). It may therefore be helpful to consider briefly the psychologicfd processes that are measured in the delayed-response paradigm as a background for studies of cognitive development. The delayed-response task was designed by the comparative psychologist Walter Hunter (Hunter, 1913) to analyze and compare the abilities of different species, including m£«i, to learn and respond to situations on the basis of stored infonnation; it was reasoned that this ability is different and dissociable from leaming and memory in situations in which all necessary information is present at the time of response. Accordin^y, in the classical visuospatial version of the test, the animal observes a food morsel being hidden in one of two locations, which are then blocked from view by the lowering of an opaque screen (Fig. 1). Following a delay period lasting from 1 to several seconds, the subject is allowed to select one of the two locations. In a variation of die test, spatial delayed alternation, the subject is required to altemate between lefl and right food wells on successive trials that are separated by delay periods. In bodi tasks, die correct choice cannot be cued by any stimuli present at the time of response; ra^er, it must be guided by internalized knowlec^e of what die subject saw or did on the previous trial. The nature of die function(s) tapped by the delayed-response tasks has been die subject of coundess studies and much speculation. Some authors have emphasized the salient mnemonic aspects of the tasks (Fuster, 1973, 1980, 1985; Jacobsen, 1936), while odiers have hi^i^te d their spatial nature (e.g., Mishkin & Pribram, 19^), and still others have focused on motor control fiinctions (Stamm, 1979; Teuber, 1972). Gurrent thinking in die field supports the view that die delayed-response task indexes the ability of an oi:ganism to guide its behavior by stored information, that is, representational memory (Fuster, 1^0, 1985; Goldman-Rakic, 19S7; Passins^iam, 1985). This type of memory is more akin to working memory and is diflferent from die type of associative memory diat is required, for example, in leaming a simultaneous visual discrimination task. A major difference between discrimination and delayed-response tasks is that in die former, a discriminative stimulus is always present to g^de respon&ng, while in the latter, behavior is guided by a representation of a prior stimulus. Also, in associative learning, a given stimulus-response asscxriation is repeatedly reinforced and strengthened, whereas in working memory tasks like delayed response, inform^on fiom one trial is irrelevant to the next trial. An importfuit jKiint is that the delayed-response deficits produced by prefrontaJ lesions in monkeys are nearly as severe at delays of 1—2 sec between cue and response as at much longer delays and, on the other hand, are absent at nil delays (Goldman, 1971). This type of evidence indicates a sharp dissociation in the neural mechanisms

Patricia S. Goldman-Rakic 603 CUE DELAY RESPONSE FIG. 1.—The three components of a delayedresponse trial. In the cue period (top panel), the monkey watches an experimenter hide a peanut half in one of two food wells and then cover bodi wells with identical cardboard plaques. A delay (middle panel) of 1 or more sec is Iben imposed by the lowering of an opaque screen that effectively blocks die animal from responding immediately. In the response phase of tiiie trial (lower panel), the screen is raised and the animal allowed to select one of the two food wells. Monkeys with lesions of the principal sulcus perform the task but do so at chance levels of accuracy. The delayed-response task is similar in all formal respects to Piaget's A 5 Test of Object Permanence (see text for furdier explanation) (from Goldman-Rakic et al., 1983). that mediate representational and associative guidance of behavior, respectively, and implicates prefrontal cortex primarily in the former. Equivalence of flayed response and Piaget's Stage IV AB Object Permanence Test.—The delayed-response task and its neural basis may be of particular interest to developmental psychologists _because of its formal similarity to Piaget's AB Stage IV Object Permanence Task and our recent demonstration that AB performance, like delayedresponse ability, depends upon the integrity of prefrontal cortejc (Diamond & GoldmanRakic, 1983). In AB, as in delayed response, the child watches as a reward is hidden in one of two spatially separated locations; a delay of a few seconds follows, and then the child is allowed to find the reward. According to Piaget, die AB test reflects the origins of intentionality and "formal operations" in children's diought processes (Piaget, 1954), and it has been used worldwide to chart milestones in human cognitive development. Aldiough each trial in the AB paradigm is the same as an individual trial in the delayed-response task, in practice there are procedural difiFerences in the ways these tasks are administered to subjects. Most important, in AB the sequence of events is under the control of the experimenter to a^reater extent than in delayed response: in AB an object is hidden at one of two locations until the subject is correct on a given trial; on the subsequent trial, the location of the bait is deliberately repeated or reversed (by the experimenter). In the classical delayed-response task, the position of the bait varies in a quasirandom schedule from trial to trial. Because of this minor procedural difference in the way the two tasks are administered, we thought it would be important to test directly whether AB depends upon prefrontal cortex as does delayed response (Diamond & GoldmanRakic, 1983). Accordingly, adult rhesus monkeys with prefrontal lesions were compared to nonnal and lesion control groups on AB administered as nearly exactly as it is given to human infents (Diamond, 1985). Some species-related differences in_ testing were, however, unavoidable. For AB testing in humans, the child is lighdy restrained on its mother's lap, whereas monkeys, freely moving, are tested from a cage. For humans, a distraction technique is used to impose a delay (Diamond, 1985); with monkeys, the delay is imposed by lowering an opaque screen between the animal's compartment and die test tray

604 ChUd Dev^opment Our results estaUished that AB, like delayed response, is impaired selectively by dorsolateial prefronttJ lesions in adult rhesus monkeys, and that die pattem of erTors displayed by the operated monkeys closely resembles that exhibited by human infants. For example, human in&nts and i^efrontal monkeys are nearly always correct when the object is hidden in the same location that was previously rewarded but perfimn near chance when the position is reversed (Diamond, 1985; Diamond & Goldman-Bakic, 1983). They have a strong tendency to repeat the previously rewarded response and are strongly guided by associative principles. The selection of a previously reiOTirded response rather than one glided by updated visual data is temied the J ^ error. During postaatal development, progressively longer delays between hiding and response are required to elicit this error in children (Diamond, 1985). Gomparing the human and monkey data, we were able to demonstrate diat the brainlesioned adult monkeys behave at the level of 7V'2-9-month-old human in^ts, making the AB error widi delays of 2-5 sec. Nomial monkeys and those with lesions of die posterior parietal cortex behave as do 12-month-old human infente, who perform correctly at these delays. On die basis of their common dependence on prefrontal cortex Mid on what we know and can dieorize about prefrontal cortex, we conclude that bodi ddayed response and AB tasks measure a common jmwess— die emergence of representational memory. This capacity may be considered a building block, if not a comerstone, of cognitive development in man. Moreover, "object permanance"—the recognition that an otgect has continuity in time and space when not in tjteuj—must depend on die elemental capacity to form representations of the outside world and to base responses on those representations In die absence of the objects diey represent. (For excellent discussion of die relevance of short-term memory processing to the temporal o^jaaization of behavior, see Fuster, 1980, 1985.) Representational processes disaUow inappropriate responses.—A cardinal feature of die behavior of human infents and of hunians and monkeys with prefrontal lesions is the strong tendency to persevenUfi a particul^ response long after it has ceased to be ^propriate. For example, a monkey with a prefroatal lesion, unlike a nramal monkey, seems to respond to the first food well &at catches its eye or to die just previously reinforced position radier than on the basis of recendy observed informadon about the location of the reward. Patients with frc»ital lobe damage are similarly perseverative, exhibiting impairments on a wide variety of tests that require suppression of prept^nt responses (or responses to distracting stimulation), including the Wisconsin Gard Sort Test (Milner, 1963, 1964), tests of selective attention (Kni^t, Hillyard, & Neville, 198?* «ni ^ Hillyard, Woods, & Neville, 1^0, 1981), die Stroop Test (Perret, 1974), the Tower of London Task (Slu^ice, 19^), and tasks that require inhibition of prepotent responses (Guitton, Buchtel, & Douglas, 1982, 1^5). Some have considered perseveration as a primary deficit attiibuteble to damage to the orbital prefrontal cortex (Fuster, 1985; Mishkin, 1964). However, I have argued feat perseveratiw behavior and distractability may be secondary consequences of file more fundamental impairment in the mechanism by which symbolic rei»esentations are accessed and held "on line" to guide a response (Goldman-RaJdc, 1987). It seems possible diat witfiout diis ability, an organism would be virtually compelled to respond refexively to stimuli present in the environment at the time of resp<mse or on the basis of prepotent response tendMicies. Further, it is easy to envision that die intensity and salience of stimulalion would be important factors goveming b^avior under such circumstances. In acMition, behavior mi£^t be regulated largely by associative c(mditioning to events that occurred in close temporal proximity. The sparing of associative memory after prefrontal irqury may help to explain why human ii^iits diaracteristically repeat a previously rewarded response rather dian execute a new more apEHK^riate response in Piaget's AB paaK^m (Diamond, 1^ ; Uzgiris & Hunt, WfS). It may also explain why frontal lobe p(#^ s can have an average store of feotual iralc^iw&on suid perform wdl on conventional IQ tests (e.g., Hebb, 1939) but be grossly deficient in how they utilize dieir representational knowfedge to guide behavior in everyday life. "Hie behavior of such patients, and to some extent of hum^i infiunts, is fragmented, la^b g clear direction and ejffiessively controH^ by extemal stimulafeon. It foUows diat die prefrontal ccatex may be necessary to overricte the teiwiency to behave stricdy on die basis of reinibrcemeat or on the basis of stirou^rtkm pre&eirt at the mome^ of response (Fuster, 1985; Goldman-R^c, 1987; ]acdbsen, 1936). By virtue o£&€ sii^ular process of wcffkiag memory, die jjirefrontal cortex nuiin^iiis access to internalized tepresentsrtiCTis for die time necessary to craniate a response or response sequence, tlie emergence of this capacity in postnatal life could

Patricia S. Goldman-Rakic 605 accomplish the dual purpose of initiating and guiding correct responses and per force disallowing or inhibiting incorrect ones that would be mediated by centers of associative conditioning. In nonhuman primates, die prefrontal cortex, in general, and the principal sulcus, in particuUir (and its human counterpart), have multiple connections with the neural centers by which these motor control Binctions can be exerted (see below and Goldman-Rakic, 1987, for friller discussion). Localization of function and domainspecific memory.—As mentioned, the principal sulcus is the cortical focus for regulation of behavior by representational knowledge of the location of objects. Monkeys lacking principal sulcal cortex exhibit deficits only on spatial delayed-response tasks (Goldman & Rosvold, 1970; Goldman, Rosvold, Vest, & Galkin, 1971) while leaving memory for the features of objects unaffected. In contrast, monkeys with lesions of the inferior convexity cortex exhibit deficits on tasks requiring working memory for visual features (e.g., color, shape) of objects rather than their location (Passingham, 1972, 1975; Mishkin & Manning, 1978; Jones & Mishkin, 1972). The conclusion from these studies is that different subdivisions of prefrontal cortex may be specialized for working memory in different informational domains. Both spatial and nonspatial working memory impairments have been reported in human patients with prefrorrtal lesions (Ghorover & Gole, 1966; Gorkin, 1965; Freedman & Oscar-Berman, 1986; Milner, 1963, 1964, 1965; Pribram, Ahumada, Hartog, & Ross, 1964; Semmes, Weinstein, Ghent, & Teuber, 1963). This is predictable, since in most studies of frontal lobe injury in man, the site of damage is not confined to one functional subdivision but more commonly extends over several. In monkeys, however, it is possible to dissociate these deficits by experimentally induced selective lesions and, further, to analyze the circuit and cellular basis of specific functions. SynomU of Prefrontal Anatomy in Adult Nonhnman Primates Gross morphology of the prefrontal association cortex.—The prefrontal cortex in monkeys lies in the anterior-most position in the cerebral hemispheres in front of the premotor and motor cortices (Fig. 2A). The three areas together comprise the cortex of the frontal lobe, widi die prefrontal cortex occupying the largest fraction (see Fig. 2A). The principal sulcus (PS) is a deep fissure extending anteriorly from the frontal pole toward die concavity formed by the arcuate sulcus, which lies at the posterior margin of the prefrontal cortex. The prefrontal, premotor, and motor subdivisions of the frontal lobe can be distinguished from one another by their cellular composition (Bonin & Bailey, 1947; Brodmann, 1909, 1925). Thus, although each subdivision is considered neocortex by virtue of the six-layered organization of its cells, the prefrontal cortex is distinctive in having a well-developed layer IV, which is virtually absent in motor cortex and poorly developed in premotor cortex. All neocortex contains a mixture of pyramidal and stellate (starshaped) cells; the former are the projection neurons of the cortex that send their axons out of the cortex to distant structures; the latter are neurons whose axons form intrinsic or local connections within die cortex. Layer IV is fonned largely of stellate cells, and thus prefrontal cortex has a larger complement of intrinsic neurons than does premotor and motor cortex. The granular fourth layer is a distinctive feature of prefrontal cortex only in primates; in all other mammalian species studied so far, the "prefix)ntal" cortex is agranular (Akert, 1964), therefore resembling more the premotor areas of the primate. Prefrontal cortex also differs from premotor and motor areas by virtue of its connectivity and functions (Goldman-Rakic, 1987). Briefly, electrical stimulation of motor and premotor areas elicits contractions of the body musculature, a fact that can be explained by direct connections of these areas with the spinal cord or brain-stem motor nuclei. Both the premotor and motor cortices contain somatotopic representations that correspond to the body parts over which they have jurisdiction. In contrast, prefrontal cortex has no direct connections to the spinal cord or brainstem motor nuclei and consequendy does not participate in a direct way in the execution, fine tuning, or metrics of motor output As might be expected, its influence over voluntary motor behavior is achieved throu^ more indirect connections with the primary motor system, including the premotor and motor cortex, and may be characterized as regulatory—related to initiation, timing, and inhibition of behavior. The principal sulcus.—Since the principal sulcus is the primary fissure in the prefrontal cortex (Fig. 2A-D) and the neural focus for delayad-response function, understanding its anatomy and physiology should provide insight into the neural substrate for regulation of behavior by stored or represen-

tationa] information. The primacy of the principal sulcus for delayed-response function has been established by at least five separate lines of evidence; (1) ablation studies (Blum, 1952; Butters, Pandya, Stein, & Rosen, 1972; Goldman & Rosvold, 1970; Mishkin & Manning, 1978); (2) pharmacolo^cal studies (Amsten & Goldman-Rakic, 1985; Brozoski, Brown, Rosvold, & Goldman, 1979); (3) microstimulation studies (Stamm, 1969); (4) electrc^hysiological recording (Fuster, 1973, 1980; Kubota & Niki, 1971; Niki, 1974a, 1974b, 1974c; Kojima & Goldman-Rakic, 1982, 1984); and (5) functional inactivation, for example, hypodiermic iractivation (Alexander & Goldman, 1978; Fuster & Alexander, 1971). These different lines of research have been extensively reviewed (Fuster, 1980; Goldman-Rakic, 1984a, 1987; GoldmanRakic, Isseroff, Schwartz, & Bugbee, 1983). Briefly, remold of the princi{»l sulcus is sufficient to produce a profound delayedresponse deficit, whereas equal-sized lesions in other portions of the front^ lolw have little effect (Goldman & Rosvold, 1970). Delayedresponse performance is disrupted in die first few seconds of the delay when electrical stimulation is applied across the principal sulcus (Stamm, 1969). Electrc^hysiological recording in animals performing delayedresponse tasks has established that principal sulcal neurons can be driven both by auditory and visual stimuli (e.g., Azuma & Suzuki, 1984; Kojima, 1980; Niki, 1972a; Suzuki & Azuma, 1985). Most important, principal sulcal neurons respond in time-locked foshion to the xnaior events of a delayed response (Fuster, 1973; Kojima & Goldman-Rakic, 1982, 1984) or delayed alternation (Kubota & Niki, 1971; Niki, 1972b, 1972c) trial. Of particular relevance is a class of cell that increases its firing selectively during the delay period of the task and in relation to die position of the stimulus. For example, a neuron may increase its dischfuge during the delay only if die cue had been on the left (or ri^t) (for review, see Fuster, 1980, 1985; also Golcbnan-Rakic, 1984a, 1987). This and other response characteristics of principal sulcus neurons make them excellent candids^s for holding visuospatial information "on line" until die correct response is made. Connectivity of the principal sulcus.— Over the past decade, die rasgor connections of the principal sulcus have been worfted out in considerable detail, to the point that relations between specific connections and specific functions can be seen and appreciated (for reviews see Goldman-R^c, 1984b, 1984c, 1987). For example, die inPatricia S. Goldman-Rakic 607 volvement of the principal sulcus in delayed response implies access to visuospatial information necessary to register the location of the food reward. Indeed, the major cortical input to the posterior two-thirds of die principal sulcus originates in the posterior parietal cortex (Fig. 2B; Goldman-Rakic & Schwartz, 1^2; Petrides & Pandya, 1984; Schwartz & Goldman-Rakic, 1984), which is the cortical center for spatial information processing (Mountcastle, Motter, Steinmetz, & Dufiy, 1984; Lynch, Mountcastle, Tdbot, & Yin, 1977). Given the mnemonic aspect of delayed-response functions, one mi^ t presume that the principal sulcus shotild interact with die hippocampus—the m^or subcortical structure that is crucial for certain forms of memory (Gohen, 1984; Squires & Butters, 1984). In support, multiple direct and indirect connections connect the principal sulcus with the hippocampus, and these connections undoubtedly play a m£^or role in assessing memories from long-term storage for use in the task at hand (Fig. 2C; Goldman-iUkic, Selemon, & Schwartz, 1984). The anatomy of motor control by which principal sulcus neurons participate in the selection or inhibition of responses has also been examined and worked out in some detail (Fig. 2D). This anatomy includes projections from the jaincipal sulcus to the caudate nucleus (Goidman & Nauta, 1977a; Selemon & Goldman-Rakic, 1985; Yeterian & Van Hoesen, 1978), connections with the motor thalamus (GoldmanRakic & Porrino, 1985; Ilinsky, Jouandet, & Goldman-Rakic, 1985), and with the deep "motor" layers of the superior colliculus (Fries, 1984; Goldman & Nauta, 1976). Thus, all circuitry exists for the components of delayed-response performance—visuospatial input (pariet^-prefrontal connections), storage/ recall mechanisms (prefrontal-hippocMnpal circuits), and motor commands (preftontal connections with motor structures). Columnar and laminar organisation of the prifuHpal sulcus.—The microarchitecture of the principal sulcus has also been studied to some degree, and several studies have revealed that diis cortex has a modular type of organization. For example, fibers originating in the parietal cortex (so-celled associational fibers) terminate in the principal sulcus as distinct vertically oriented columns about onehalf millimeter in width (Goldman & Nauta, 1977b). These columns altemate with equalsized colunms of fibers from the contralateral principal sulcus (so-called callosal projections) (Fig. 3, Goldman-Rakic & Schwartz, 1982). The cortex, as has been mentioned, is organized into six layers, and both callosal

608 Child Development and associational fibers tend to terminate selectively in layers IV and I, while associational fibers additionally terminate in layer VI (see Fig. 3 for details). The cortex also has a radial or horizontal geometry due to its distinct six-layered organization. The significance of the layering pattem is that cells in the specific layers that are targets of incoming callosal or associational afferents have distinctive projection targets in subcortical and/or other cortical structures. For example, as shown in Figure 3, pyramidal neurons in layer III project primarily to other cortical areas, bodi widiin the same (associational neurons) and opposite (callosal neurons) hemispheres. While over 80% of callosal and associational neurons originate in layer III, layer V is the msyor source of projections to the caudate nucleus and putamen, to the colliculus, and to other subcordcal structures; neurons in layer VI project selectively to the thalamus (Fig. 3). Knowing these facts, one can begin to appreciate the synaptic architecture and wiring diagrams underlying a specific cortical function. Prenatal Development of Prefrontal Connections Background for prenatal studies.—It is reasonable to assume that adult function can emerge only if the proper connections and circuitry necessary to carry out that fimction are established. The principal sulcus and its interconnections provide a natural model system for the study of the biological basis of die particular type of cognitive capacity indexed by delayed-response tasks, namely, the guidance of behavior by stored representations. Although in theory it is possible to begin the developmental study of structure-function relations at birth or at any other arbitrary point in infancy, the processes and mechanisms of development are complex, onierly, and synchronized and can best be appreciated only by comprehensive analysis of antecedent causes. Accordingly, the study of prefrontal cortex development in my laboratory includes analysis of the earliest embryonic ages that it is feasible to study in primates. It is important to realize that the critical cellular events that take place at or after birth in small mammals, for example, the rat, occur much earlier in the primate, well before birth (for fuller discussion of these events, see Goldman-Rakic, 1986; Rakic & Goldman-Rakic, 1982). It was therefore necessary to develop techniques for prenatal surgery and prenatal intervention that could be applied to the primate brain (for review, see Rakic & Goldman-Rakic, 1984). Our focus has been on the outgrowdi of axons and the establishment of synaptic connections between the key areas that comprise the system underlying delayed response. Autoradiographic methods for studying prefrontal connections.—Very few studies have ever been conducted on the development of connectivity in the primate brain, and it was the availability of the autoradiographic method in conjunction with prenatal surgery that made it feasible to trace connections in fetal monkeys. Before this method, connections were traced by performing rather large lesions of structures, and after an appropriate survival period, examining brain sections for degenerating axons and terminals (that could be visualized because they selectively impregnate silver). This mediod had several drawbacks that made it particularly difficult to apply to developing animals. The optimal survival time for visualizing the products of degeneration had to be worked out empirically and separately for every age point and neural system (Leonard, 1973). The reliability of the silver impregnation varied with investigators. Finally, the resolution of connections was intrinsically poor because one could describe projections only between large areas. Golumnar distribution of connections, for example, was not discovered with silver-impregnation methods. By contrast, the autoradiographic technique was a highly reliable method that gave clear and consistent results. Small quantities of radioactive isotopes are injected into designated areas; the size of the area injected can be controlled by the volume of isotope injected. Neurons at the site of injection absorb die mdiolabeled amino acids into their cell bodies. In the cell body, the amino acids are converted into proteins by normal protein synthesis, and these proteins are transported from the cell dirough its axon to the terminal region of die cell. From knowledge of cell biology, the precise survival times optimal for transport to occur can be accurately predicted to optimize visualization of terminal fields (the distribution of labeled axons in target stmctures) and for determination of die pathways by which the axons reach their targets. Sections cut throu^ the brain are mounted on slides that are dipped in photographic emulsion in the dark; the emulsion is exposed only by the beta emissions radiating from labeled cells, axons, and terminals that may be present within any given section. After 8— 12 weeks, the slides are developed and the exposed areas appear as darkened grains

610 Child Development above the structure in which radioactivity was present (for examples, see Goldman & Nauta, 1977a, 1977b; Goldman-Rakic, 1981a). Development of prefrontal efferents.— In die studies mentioned, prenatal surgery was performed on timed-pregnant rhesus monkeys carrying fetuses ranging from 69 embryonic days (E69) to 152 embryonic days (E152) and on several newbom monkeys. In diis species, the average gestation lasts 165 days. The fetuses were exposed dirough an incision in the uterus and were operated on in a manner similar to postnatal neurosurgeiy. Although the primary fissures do not develop fully until the last third of gestation, the principal sulcus can be visualized as a small indentation on the dorsoktera] surface of the frontal lobe; in younger fetuses, the iiyection was placed in die center of the dorsolateral part of the lobe. After microinjections of radioactive amino acids were made in the prospective principal sulcus, the fetal tissues were sutured and the fetus returned to the uterus, which was also sutured. The fetuses survived 1-3 days, sufficient time for transport to occur in die padiways under investigation. These autoradiographic Investigations were designed to provide basic information on timetables for the outgrowth of corticocortical (callosal and intrahemispheric) and selected cortico-subcortical connections. Surprisingly, perhaps, precise information on the development of connectivity was not available for any species, since only gross approximations and wide limits can be deduced from analysis of nervous tissue prepared with conventional stains. Another basic question concemed the mode of development of the columnar pattem of callosal innervation characteristic of the adult pathways. We wondered whether diis input was initially diffusely distributed in the cortex before becoming segregated into distinct colmnnar territories in a manner similar to the bii^asic development of afferent territories in the visual cortex (Hubel & Wiesel, 1977; Rakic, 1976). Thorough examin^on of the youngest fetus injected, E69, provided no evidence that callosal or intrahem^pheric axons were yet present in the vicinity of their target structures (Fig. 4). Although labeled axons could be seen entering the callosum from the injected hemisphere, none reached and were present in the opposite hemisphere at this age. In contrast, labeled fibers were already evident in the caudate nucleus, which is part of the basal ganglia and also in die thalamus E69-E70 P4-PII FIG. 4.—Gallosal fibers at different embryonic (£) and postnatal (P) ages. The first number beneatii each drawii^ indicates the age in days when Uie animal was injected witii radioactive tracers, and the second number of tihe pair indicates the ^ e in days when it was sacrificed. Callosal fibers do not reach the contralateral hemisphere until after E70 and do not enter the cortica] plate in significwit numbers before E123. Callosaj axons invade the cortex between E123 and E152. At around E135 (not shown) and E152, they are already well segregated into the modular pattem chaiacteristic of the neocortex in the postnatal monkey (from Goldman-Rakic, 1981b)

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