organization of rat vibrissa motor cortex and adjacent areas...

Organization of Rat Vibrissa MotorCortex and Adjacent Areas According to

Cytoarchitectonics, Microstimulation,and Intracellular Stimulation of

Identified Cells

MICHAEL BRECHT,* ANDREAS KRAUSS, SAJJAD MUHAMMAD,

LALEH SINAI-ESFAHANI, SEBASTIANO BELLANCA, AND TROY W. MARGRIE

Department of Cell Physiology, Max-Planck Institute for Medical Research,D-69120 Heidelberg, Germany

ABSTRACTThe relationship between motor maps and cytoarchitectonic subdivisions in rat frontal

cortex is not well understood. We use cytoarchitectonic analysis of microstimulation sites andintracellular stimulation of identified cells to develop a cell-based partitioning scheme of ratvibrissa motor cortex and adjacent areas. The results suggest that rat primary motor cortex(M1) is composed of three cytoarchitectonic areas, the agranular medial field (AGm), theagranular lateral field (AGl), and the cingulate area 1 (Cg1), each of which representsmovements of different body parts. Vibrissa motor cortex corresponds entirely and for themost part exclusively to AGm. In area AGl body/head movements can be evoked. In posteriorarea Cg1 periocular/eye movements and in anterior area Cg1 nose movements can be evoked.In all of these areas stimulation thresholds are very low, and together they form a completerepresentation of the rat’s body surface. A strong myelinization and an expanded layer 5characterize area AGm. We suggest that both the strong myelinization and the expandedlayer 5 of area AGm may represent cytoarchitectonic specializations related to control ofhigh-speed whisking behavior. J. Comp. Neurol. 479:360–373, 2004. © 2004 Wiley-Liss, Inc.

Indexing terms: whisker; motor maps; frontal cortex

It has long been recognized that the mammalian neo-cortex is functionally heterogeneous and can be subdi-vided into multiple areas. Ideally, cortical areas are delin-eated based on convergent results from multipleapproaches, such as cytoarchitectonics, connectivity, to-pography, physiology, and behavioral tests combined withmanipulation of neural activity in the area of interest (vanEssen, 1985).

The primary motor cortex (M1) was one of the firstcortical areas that could be delineated with a functionalmapping approach, namely, electrical surface stimulation(Fritsch and Hitzig, 1870). The functional maps of M1derived from surface stimulation were confirmed by lesionapproaches (Ferrier, 1875). M1 is a large frontal area thatrepresents movements and is common to all mammalianspecies thus far studied (Woolsey, 1958; Creutzfeld, 1989;Asanuma, 1989). Work from a wide variety of investiga-tors suggests that M1 can be identified based on the fol-lowing criteria: 1) its agranular cytoarchitectonic appear-

ance, 2) its low (�50 �A) stimulation thresholds forintracortically evoked movements, 3) a topographic repre-sentation of muscles, and 4) a complete representation ofthe body musclelotopy.

The functional organization of rat primary motor cortexhas been investigated in a number of studies (Hall andLindholm, 1974; Gioanni and Lamarche, 1985; Neafsey et

Grant sponsor: Max-Planck-Society; Grant sponsor: Wellcome Trust;Grant number: 070067/Z/02/Z.

Michael Brecht’s current address is Department of Neuroscience, Eras-mus MC, Postbus 1738, 3000 DR Rotterdam, The Netherlands.

*Correspondence to: Michael Brecht, Department of Neuroscience, Eras-mus MC, Postbus 1738, 3000 DR Rotterdam, The Netherlands.

E-mail: [email protected] 11 December 2003; Revised 8 June 2004; Accepted 26 July 2004DOI 10.1002/cne.20306Published online in Wiley InterScience (www.interscience.wiley.com).

THE JOURNAL OF COMPARATIVE NEUROLOGY 479:360–373 (2004)

© 2004 WILEY-LISS, INC.

al., 1986; Miyashita et al., 1994; Huntley, 1997). Micro-stimulation studies showed that eye movements are rep-resented in a long medial stripe, bordered laterally by asimilarly elongated vibrissa area. Posterolateral from thevibrissa representation, trunk, tail, and hindlimb move-ments can be evoked; lateral from it forelimb movementsare represented, and anterolateral tongue and jaw move-ments are evoked. Although not all details of such motormaps are identical, there is a remarkably good agreementon the stereotactic coordinates of various body partsamong studies.

Anatomical studies have led to a relatively good consen-sus about cytoarchitectonic areas and their borders in ratfrontal cortex (Zilles et al., 1980; Donoghue and Wise,1982; Neafsey et al., 1986; Zilles and Wree, 1995). All ofthese studies agree on 1) the existence at least two largecytoarchitectonic areas (AGm and AGl; see Table 1) on thedorsal surface of the rat’s frontal cortex and 2) the roughlocation of the border between these two areas. The moremedial area (AGm) is medially flanked by Cg1 (see Table1), which is situated in the medial bank, and the lateralarea (AGl) is laterally flanked by the primary somatosen-sory cortex.

It is not clear how motor maps and cytoarchitectonicmaps are related in rat frontal cortex. First, the originalmotor map by Hall and Lindholm (1974), does not super-impose well upon cytoarchitectonic boundaries. Second,combined studies of motor maps and cytoarchitectonicshave led to conflicting views about the organization of M1.An initial study by Donoghue and Wise (1982) suggestedthat area AGl corresponds to M1 and contains a more orless complete representation of the body surface that in-cludes the vibrissa representation. In this scheme, areaAGm was viewed as a higher order motor area. In contrastthe cytoarchitectonic/motor maps of Neafsey et al. (1986)and colleagues indicated that no vibrissa representation isfound in area AGl. In the partitioning scheme of Neafseyand colleagues, area AGm represents both vibrissa and eyemovements and is viewed as a frontal eye field analogarea, i.e., as a specialized motor representation separatefrom M1.

The conflicting views on the relationship of cytoarchi-tectonics and motor maps indicate the need for improvedmethods for superimposing motor maps upon cytoarchi-tectonic data. The intracellular stimulation of morpholog-ically identified neurons may provide this kind of informa-tion. We recently observed that intracellular stimulation

of cells in the vibrissa motor cortex evokes small whiskermovements (Brecht et al., 2004). It is thus possible todetermine the location of vibrissa-movement-related neu-rons at the level of single neurons. Additionally, the den-dritic morphology of the recovered cells allows determina-tion of the location on the brain surface to which the apicaldendrite of the cell is directed. In this way it is possible toconstruct a cell-based brain surface map of movement. Inthis study, we combine this cell-based technique with mi-crostimulation and cytoarchitectonic analysis. The goal ofour study is twofold: 1) to derive combined motor andcytoarchitectonic maps of vibrissa motor cortex and adja-cent areas and 2) to identify cytoarchitectonic specializa-tions of vibrissa motor cortex.

Our results show that vibrissa motor cortex correspondsentirely and for the most part exclusively to area AGm.This area is characterized by a strong myelinization andan expanded layer 5. According to our results, rat M1 iscomposed of three cytoarchitectonic areas, Cg1, AGm, andAGl, each of which represents movements of different bodyparts. In all of these areas, stimulation thresholds arevery low, and together they form a complete representa-tion of the rat’s body surface.

MATERIALS AND METHODS

Preparation

We used standard surgical and electrophysiologicaltechniques (Brecht and Sakmann, 2002; Margrie et al.,2002). Animals (n � 70) were anesthetized with ketaminehydrochloride (90 mg/kg ip)/xylazine (5 mg/kg ip) for sur-gical anesthesia. All pressure points and the skin incisionwere infused with lidocain. During M1 stimulation, ani-mals received supplemented doses of ketamine (20 mg/kg)and acepromazine (0.02 mg/kg im) as needed. Vibrissamotor cortex (A1–A2.5, L1–L2.5 relative to bregma) wasexposed, and extracellular and intracellular stimulationwas applied. All experimental procedures were carried outaccording to the animal welfare guidelines of the Max-Planck-Society.

Microstimulation

ICMS stimulation (Asanuma and Sakata, 1967) wasonly effective in evoking whisker movements when theanimals were lightly anesthetized and displayed at leastsome minimal level of spontaneous whisker movementswith amplitudes �0.5°. With animals under deeper anes-thesia stimulation, currents of up to several hundred �Adid not evoke movements. We proceeded with the experi-ments only if stimulation currents �65 �A evoked move-ments. Extracellular stimulation consisted of 100 0.3-msec-long monophasic cathodal stimulation pulsesapplied at a frequency of 333 Hz, resulting in 300-msecstimulation trains. In our anesthetized preparation, pulsetrains of only 10 pulses evoked similar movements (datanot shown); this is not surprising, because, for near-threshold stimuli, evoked movements were usually briefand restricted to the beginning of the stimulation train(see also Brecht et al., 2004). Current was deliveredthrough a stimulus isolator connected to an extracellularstimulation pipette (tip resistance 0.5–1 M�) at a depth of1,500 �m below the pial surface at a rate of 0.1 or 0.2 Hz.

Abbreviations

AGl agranular lateral areaAGm agranular medial areaCC corpus callosumCg1 cingulate area 1Cg3 cingulate area 3ICMS intracortical microstimulationL1 cortical layer 1L2 cortical layer 2L3 cortical layer 3L4 cortical layer 4L5 cortical layer 5L6 cortical layer 6M1 primary motor cortexM2 secondary motor cortexS1 primary somatosensory cortexWM white matter

361TOPOGRAPHY OF RAT M1

Intracellular stimulation

Intracellular stimulation consisted of 5- or 10-msec cur-rent steps for evoking individual APs in sequences asspecified in the text. Intracellular stimulation was deliv-ered at a rate of 0.1 (most cases) or 0.2 Hz for 10–30 trialsper experimental condition. Recordings were made withlong taper patch pipettes with tip resistances of 4–7 M�pulled from borosilicate glass tubing (Margrie et al.,2002). Pipettes were filled with (in mM): K-gluconate 130,Na-gluconate 10, HEPES 10, phosphocreatine 10, MgATP4, Na2ATP 2, GTP 0.3, NaCl 4, and 0.4% biocytin at pH7.2. Among 55 M1 recordings of regularly spiking neurons,five cells were excluded from analysis because fewer than10 stimulation trials with 10 APs injected at 50 Hz weremade. Six recordings from M1 were excluded from analy-sis because the anesthesia was considered to be too deepbased on the absence of even small whisker movements(criterion: fewer than one �0.5° whisker movement per 20seconds). Thus, 44 stimulation experiments with regularlyspiking or intrinsically bursting cells and three experi-ments with fast-spiking neurons entered our analysis. Wevideotaped whisker movements from the top andstimulated/analyzed only laterally oriented whiskers rows(rows C, D, and E). All evoked whisker movements werevideotaped, and the angular movements of whiskers ofinterest were quantified in frame-by-frame analysis ofvideotapes. The significance of the evoked movements wastested in the following way. For each stimulation trial(10–30 per cell), we determined the peak to peak ampli-tude of movements in the 1 second just after AP initiationand of spontaneous movements during the 1 second im-mediately before stimulation and assessed the differencebetween the two measurements by a two-tailed, pairedt-test; P � 0.05 was considered significant. In all cases inwhich we observed a significant difference in pre- andpoststimulation amplitudes, poststimulation amplitudeswere greater.

Unless noted otherwise, all the data presented in thepaper refer to the “best whisker” determined by ICMS.Movements were sampled at a rate of 25 Hz, which isgenerally sufficient to sample the rather slow whiskermovements under anesthetic conditions. In two experi-ments, we sampled movements at 150 Hz and obtainedresults identical to those obtained when we analyzed thesame experiments with lower sampling rates.

Histology

Upon the completion of physiological recordings, ani-mals were perfused transcardially (after an additionaldose of ketamine/xylazine) with 0.1 M phosphate-bufferedsaline (PBS) at pH 7.2, followed by a solution of 4% para-formaldehyde. The brain was removed from the skull,immersed in fixative, and sectioned. Slices (100 or 150 �mthick) were then processed with the avidin-biotin-peroxidase method (Horikawa and Armstrong, 1988) to

reveal cell morphology. Subsequently, biocytin-labeledneurons were reconstructed with Neurolucida software(MicroBrightField, Colchester, VT).

In a fraction of brains, cytochrome oxidase stainingaccording to Wong-Riley (1979) was performed. Nisslstains were performed according to the protocol specifiedby Paxinos and Watson (1998). Myelin was visualized bythe staining procedure described by McNally and Peters(1998). Digital images of sections were processed in AdobePhotoShop for optimal luminance and contrast.

RESULTS

Cytoarchitectonic areas and terminology

All cytoarchitectonic studies undertaken so far agreethat the rat’s frontal cortex contains a number of cytoar-chitectonically distinct areas. Although most authorsagree on the major boundaries in frontal cortex, severalpartitioning schemes have been suggested (Krieg, 1946;Krettek and Price, 1977; Zilles et al., 1980; Donoghue andWise, 1982; Zilles and Wree, 1995). These partitioningschemes differ mainly in the extent to which individualareas are subdivided into smaller units. To highlight thesimilarities between these partitioning schemes and toclarify terminological issues, an isoterminology account ofvarious cytoarchitectonic studies is given in Table 1. Forthe areas on the dorsal surface, we follow the nomencla-ture of Donoghue and Wise (1982), and for areas of themedial bank we follow Zilles and Wree (1995). We adoptthese particular terminologies because they are relativelywidely used and because both terminologies explicitly de-note cytoarchitectonic divisions rather than completefunctional maps, as is often implied with terms such asM1, M2, etc.

The areas dealt with in our study thus include (fromlateral to medial) the somatosensory cortex S1, theagranular lateral area (AGl) of Donoghue and Wise (1982),the agranular medial area (AGm) of Donoghue and Wise(1982), and the cingulate area 1 (Cg1) and cingulate area3 (Cg3) of Zilles and Wree (1995). All but one boundarybetween these areas can be easily distinguished in Nisslstains, and the existence of these boundaries is largelyundisputed.

The boundary between S1 and area AGl is defined by asharp decrease in layer 4 (L4) thickness and a prominentincrease in L5 thickness, typical for a sensory-motorboundary (see also Kim and Ebner, 1999). The boundarybetween area AGl and AGm is also conspicuous and ischaracterized by a dorsalward expansion of L5 and re-duced thickness of L3 in area AGl. The AGl/AGm border isof particular importance in the present study, so we in-vestigated its appearance in detail. We found that theAGl/AGm transition can be quite abrupt, that is, occur inless than 100 �m (see Fig. 2); semiabrupt, with bothstrong change of the laminar patterning within 100 �m

TABLE 1. Equivalent Nomenclature for Rat Cortical Areas

Area(this study)

Krettek and Price,1977

Zilles et al.,1980

Donoghue and Wise,1982

Zilles and Wree,1995

Paxinos and Watson,1998

AGl PrC1 Prc1–2 AGl Fr1 M1AGm PrCm Prcm, Pr3 AGm Fr2 M2Cg1 ACd C1 Cg1 Cg1Cg3 PL C4 Cg3 Cg3,PrL

362 M. BRECHT ET AL.

and more gradual change of the laminar patterning occur-ring over 200–300 �m (see Fig. 4); or continuous, with amore or less smooth transition of the laminar patterningoccurring over 200–300 �m (see Fig. 5).

The boundary between area AGm and Cg1 is bestrecognized by the pronounced increase in thickness ofL1 and L2 in area Cg1. The border between area Cg1

Fig. 1. Dendritic morphology and location of whisker-movement-related pyramidal neurons in the rat motor cortex. Morphology andlocation of five deep layer (L5 and L6) pyramidal neurons, in whichintracellular stimulation (initiation of 10 APs at 50 Hz) evoked sig-nificant whisker movements (see Materials and Methods). All fiveneurons were recorded roughly 1.5 mm anterior to bregma and 1–2.5mm lateral from midline. The morphology of biocytin-labeled neuronswas reconstructed with Neurolucida software and cells recorded in

different brains were superimposed on a representative brain section.Care was taken to position correctly cells with respect to layer, cur-vature, and mediolateral position in the motor cortex. As indicated bythe dashed lines, all cells were situated in area AGm; however, theexact position of areal boundaries varied from brain to brain anddistance to areal boundaries is, therefore, only approximately correctfor individual cells. Scale bar � 500 �m.

TABLE 2. Areal Location of Whisker-Movement-RelatedDeep Layer Cortical Neurons

Area Cg1 AGm AGl

Number of cells filled and recovered at MS sitesat which whisker movement was evoked

0 34 0

Number of identified cells in which intracellularstimulation evoked significant whiskermovements

0 7 0


and Cg3 is more difficult to delineate. The two areas canbe differentiated by a number of subtle demarcations,including a reduced overall thickness of Cg3, a thickerL2 in Cg1, a thicker L1 in Cg3, and a more denselypacked L2 and L5 in area Cg3. All of these areas can bedistinguished by further histological criteria, and suchfindings have been discussed in detail elsewhere (Zillesand Wree, 1995).

Whisker-movement-related cells are foundin area AGm

In our experiments, we first applied ICMS to deep cor-tical layers (1,500 �m below the pial surface) to identifythe M1 region representing vibrissa movements. One orseveral penetrations with an extracellular stimulationelectrode were performed 1.5–2.5 mm anterior to bregma

Fig. 2. The lateral border of vibrissa motor cortex corresponds tothe lateral border of area AGm. A: Extracellular stimulation site.B: Movements evoked at a stimulation current intensity of 60 �A. Forsimplicity, only whiskers that were deflected in response to stimula-tion are illustrated. C: Top: Movements evoked at a stimulationcurrent intensity of 40 �A. Bottom: Movement of whisker E2 (themost strongly deflected whisker). An averaged trace of 10 stimulation

trials is shown. f, Forward, b, backward. D: Cell stimulated intracel-lularly. E: Top: Diagram of movements evoked by intracellular stim-ulation. Bottom: Movement of whisker E2. An averaged trace of 10stimulation trials is shown. Dashed line in C and E indicates thestimulation onset. The brain section shown here was also used for thesuperimposition of cells in Fig. 1. Scale bars � 500 �m.


Figure 3


and 1–2.5 mm lateral from midline. These stereotaxiccoordinates correspond to the lateral parts of area AGmand the medial parts of area AGl (Paxinos and Watson,1998). In about 80% of experiments (29 of 37), ICMS at thefirst stimulation site tested evoked whisker movements.In about 20% of experiments (8 of 37), ICMS at the firststimulation site tested evoked forepaw movements; inthese experiments, we continued searching for whisker-specific ICMS sites, and we always found such sites me-dial from the sites that evoked paw movements. Afterhaving identified a whisker-specific site by extracellularstimulation, we withdrew the stimulation electrode andobtained whole-cell recordings in the vicinity of the extra-cellular stimulation site (an estimated maximal distanceof �200 �m horizontally and �500 �m vertically). Weobtained 47 such recordings (44 from regular spiking andintrinsic bursting cells, three from fast spiking cells) in L5and L6. AP initiation (10 APs at 50 Hz or 100 Hz) evokedsmall whisker movements in about 20% of these cells(Brecht et al., 2004), confirming that these neurons rep-resented whisker movements. For 34 of these recordings,we were able to recover the morphology of the respectiveneuron. We determined whether the cell was situated inarea AGm or AGl based on the dorsalward extension of L5in area AGm (Donoghue and Wise, 1982), which could bevisualized in each of the respective sections. Figure 1shows the morphology and location of some of the pyrami-dal neurons in which intracellular stimulation (10 APs at50 Hz or 100 Hz) evoked whisker movements. As shown inFigure 1 and quantified in Table 2, all of these cells werelocated in area AGm. Even in cases in which we did notrecover the recorded neuron, we usually observed a diffusebiocytin labeling around the presumptive recording site,which was invariably in area AGm. Extracellular and in-tracellular stimulation combined with cell recovery thusdemonstrate that whisker-movement-related cells arefound in are AGm. All whisker-movement-related neuronswere identified in area AGm, although we searched forthem in an area that stereotaxically encompassed botharea AGm and area AGl. This observation indirectly indi-cates an absence of whisker-movement-related sites inAGl.

Lateral border of vibrissa motor cortexcoincides with the lateral border of area AGm

More direct support for the idea that area AGm but notarea AGl represents whisker movements came from ex-periments in which we could directly correlate physiolog-ical and cytoarchitectonic boundaries. As shown in Figure2, we observed that ICMS at high current intensities (60�A) could evoke movements of both whiskers and forepaw

(Fig. 2A,B), whereas at lower intensities it caused move-ment of E-row whiskers (Fig. 2C). These stimulation ef-fects suggested that the stimulation site was close to thephysiological boundary between paw and whisker repre-sentation, inside the whisker area. Subsequently, we ob-tained a whole-cell recording close to the stimulation site(Fig. 2D). Consistent with this cell being in the whiskermovement representation, intracellular stimulationevoked (Fig. 2E) whisker movements. Figure 2 also dem-onstrates that intracellular stimulation (Fig. 2E) leads toslower onset and more prolonged movements (Fig. 2C)than extracellular stimulation, as we reported earlier(Brecht et al., 2004). The greater baseline variability forintracellular stimulation (Fig. 2E) was related to the factthat the animal was in this case less deeply anesthetizedduring the intracellular stimulation than during the ex-tracellular stimulation. Histological reconstructionshowed that the ICMS site (Fig. 2A) and the cell (Fig. 2D)were located laterally in area AGm, close to the border ofarea AGl. It is important to note that in this case theAGm–AGl border was sharply delineated by an abruptdorsalward expansion of L5 (data not shown). Similarobservations were made in two further experiments, inwhich we observed coactivation of whisker and paw atstimulation currents �60 �A and in which whisker-related cells were subsequently identified in AGm close tothe AGl border. These data, although restricted to a verysmall sample, argue against the idea that area AGl con-tains a whisker representation. Both the selective locationof whisker-movement-related cells in area AGm and theidentification of whisker-movement-related cells at thephysiological vibrissa/paw boundary suggest that the cy-toarchitectonic border between area AGm and area AGlcorresponds to the physiological border between whiskerand paw movement representations.

Medial border of vibrissa motor cortexcoincides with the medial border of area AGm

Most of the extracellular and intracellular stimulationexperiments considered so far were directed toward thelateral parts of the vibrissa representation and of areaAGm. To determine the medial border of vibrissa motorcortex we therefore conducted a series of extracellularstimulation (n � 4) experiments in which we systemati-cally applied ICMS and histological reconstruction ofstimulation tracts in areas of the medial bank.

In these experiments, multiple perpendicular (dorso-ventral) stimulation tracks were made at 1 mm lateralfrom the midline, regularly spaced along the rostrocau-dal axis. The results of a representative experiment areillustrated in Figure 3. We observed in these penetra-tions a stereotyped sequence of evoked movements (Fig.3A). We observed, in the more posterior region of thestimulation area, the following responses with increas-ing penetration depth. Superficially, in the curved partsof cortex, low-threshold (�60 �A) whisker movementswere evoked, followed by low-threshold (�60 �A) eyeand/or periocular movements, which were observed atthe transition from the curved cortex to the medialbank. These responses were followed by high-threshold(�60 �A) eye and/or periocular movements and finallyunresponsive sites deep in the medial bank. We ob-served in the anterior (�3 mm rostral from bregma)region a sequence of low-threshold whisker movements,low-threshold nose movements, and unresponsive sites.

Fig. 3. Motor maps of the medial bank of the rat cortical hemi-sphere. A: Left: Raw stimulation map from a microstimulation exper-iment. All penetrations were vertical and were made 1 mm lateralfrom midline. Arrows in the green squares indicate the direction ofwhisker movements. Capital letters in green squares indicate thewhisker row deflected at the minimal current for a visible movement.Right: Superimposition of the stimulation map and the rat brain. a,Anterior, p, posterior. B: Left: Cell based projection of the deep layerstimulation map shown in A on the surface of the rat brain. Cytoar-chitectonic areas determined from histological reconstruction are un-derlaid. The arrow marks the plane of section shown in Figure 4.Right: Position of the stimulated area in the rat brain.


To understand better how the topography of motor re-sponses mapped onto the curved surface of motor cortex,we projected each deep layer stimulation site to the pointof the cortical surface, to which the apical dendrites of therespective cells were pointing (Fig. 3B). For determiningthe vertical organization of the respective cortical sites,our orientation was at the vertical alignment of cell bodiesin the Nissl stains, which is in register with the respectiveapical dendrites. In the resulting projection scheme, eachstimulation site is projected to that point on the corticalsurface to which putative apical dendrites of the stimu-lated cells were projecting. From such a cell-based projec-tion of deep-layer stimulation sites (Fig. 3B), it becameobvious that the stereotaxic location of whisker, low-threshold eye/periocular, and high-threshold eye/periocular movement sites corresponded well with the lo-cation of cytoarchitectonic areas AGm, Cg1, and Cg3,respectively.

The histological reconstruction of individual stimula-tion tracks fully supported the idea that the medialborder of vibrissa motor cortex corresponds to the bor-der of area AGm and Cg1 (Fig. 4). The positions ofelectrolytic lesions along such tracks indicated an ex-cellent correspondence of cytoarchitectonic areas andphysiological boundaries (Fig. 4). These data showedthat the medial parts of area AGm corresponded to alow-threshold whisker movement area. The posteriorparts of area Cg1 corresponded to a low-threshold eye/periocular movement area, the anterior parts of areaCg1 corresponded to a low-threshold nose movementarea, and area Cg3 corresponded to a high-thresholdeye/periocular movement area.

In all our experiments, eye/periocular and whiskermovement representations were spatially segregated. Inthe stimulation map shown in Figure 3A as well as inother ICMS experiments, whisker and eye movementswere never intermingled; eye/periocular movements werealways found medially/ventrally from whisker move-ments. As pointed out above, these movements were rep-resented in cytoarchitectonically distinct areas. Despitethe high current intensities applied in area Cg3, theevoked eye/periocular movements were generally verysmall, and at several putative Cg3 sites no such move-ments were evoked (Figs. 3, 4).

Types of movements evoked by stimulationof vibrissa motor cortex

Our observations with respect to the topography andmotor characteristics of movements evoked fromvibrissa motor cortex were in good agreement withthose of previous investigators (Hall and Lindholm,1974; Gioanni and Lamarche, 1985; Neafsey et al., 1986;Miyashita et al., 1994; Huntley, 1997). The minimal(threshold) stimulation currents required for evokingjust-visible movement were 32 � 22 �A (mean � SD).The number of moving whiskers varied as a function thestimulation site, and multiwhisker movements oftenencompassed the whiskers of a row. At threshold in 25%of stimulation sites, single or dual whisker movementswere evoked; in 25% of cases, movements of whole whis-ker rows were evoked; and, in 50% of sites, movementsof multiple rows were observed. The size of movement

fields monotonically increased with decreasing depth ofanesthesia and also varied with the type of anesthesia.Thus, single or dual whisker movements were preferen-tially evoked after supplementation with acepromazineand were only rarely seen in animals that receivedexclusively a ketamine/xylacin anesthesia.

In most instances (78%, 84 of 108 cases in which theinitial movement direction could unambiguously deter-mined) just-above-threshold high-frequency ICMSevoked an initial backward movement of the whiskers.At the remaining 24 sites high-frequency (100 Hz or 333Hz pulse repetition rate) ICMS evoked movements withan initial forward/protraction component. Such back-ward and forward movement sites were spatially segre-gated. Forward sites often formed small “islands” at themedial or lateral borders of AGm but had no strictlyreproducible localization. An example of this organiza-tion is illustrated in Figure 3A, in which all of therelatively few forward sites are nested together in theanterior part of the stimulation map. As for intracellu-lar stimulation (Brecht et al., 2004), we observed areversal of the evoked movement direction when low-frequency (10 or 20 Hz pulse repetition rate) ICMS wasapplied. These observations may indicate that individ-ual vibrissa motor cortical neurons exert control overboth the intrinsic whisker muscles involved in whiskerprotraction and the extrinsic whisker muscles involvedin whisker retraction (Dorfl, 1982; Wineski, 1985; Bergand Kleinfeld, 2003a).

In our analysis of whisker movements, we focused onchanges in vibrissa position and paid less attention to thequestion of whether such positional changes came aboutby movements of the whole whisker pad or by movementof individual whisker follicles. Informal observation sug-gested that most of the observed movement resulted fromfollicle movements, but this question deserves further in-vestigation. We often observed bilateral whisker move-ments, particularly at higher stimulation intensities, but

Fig. 4. Reconstruction of a stimulation track in the medial bank.Diagram of a stimulation track in a coronal section. Areal and laminarboundaries as determined from Nissl stain have been highlighted. Atleft is a list of evoked movements with threshold currents. L, electro-lytic lesions. The rostrocaudal position of the plane of section is shownin Figure 3. Scale bar � 1 mm.


the representation of ipsilateral whisker movements wasnot systematically studied here.

Microtopography of vibrissa motor cortex

Evoked whisker movements showed a clear topo-graphic organization, the posterior whiskers being rep-resented more caudally and the more dorsal whiskersbeing represented more medially/ventrally. Two factorscomplicated the analysis of motor topography. The firstproblem was the variable and occasionally large sizemovement fields. The second problem for analyzing mo-tor topography was the curved surface of AGm. Thus, forperpendicular penetrations, the utmost care had to be

taken to stimulate at a similar laminar depth, becausevariations in stimulation depth result in distortions ofthe motor topography. For penetration tracks parallel tothe surface of AGm, we never observed a violation oftopography; i.e., more dorsal whiskers were always rep-resented medially from ventral whiskers (Fig. 3A). Theposterior whiskers (straddlers and whiskers 1 and 2)dominate the whisker representation of area AGm andtake up more than half of the motor map (Fig. 3A).Roughly speaking, movements of whisker rows A and Btend to be represented in the medial bank, whereasmovements of rows C–E tend to be represented by cellsoriented toward the dorsal surface of the brain.

Fig. 5. Nissl, myelin, and cytochrome C stain of rat motor cortex.Three adjacent 100-�m sections from rat motor cortex are shown.A: Nissl stain. B: Myelin stain (after McNally and Peters, 1998). Adark silver precipitate reveals myelin. C: Stain for cytochrome C

oxidase activity. Increased activity is revealed by a dark color.D: Same as in A, but at higher magnification and with highlightedlayer boundaries. Scale bars � 1 mm.


Figure 6


Cytoarchitectonic specialization of vibrissamotor cortex

Area AGm was distinguished from neighboring areas bya number of cytoarchitectonic features, which may be re-lated to its function in the control of whisking behavior.The most conspicuous feature of area AGm was its lami-nation pattern. An increased thickness of L5 and a de-creased thickness of L3 characterized AGm, and both thesechanges made it appear that L5 expanded dorsalwardtoward the pial surface (Figs. 2A, 4, 5A,D). In the caseshown in Figure 5A,D, a very smooth change (i.e., a verybroad �300-�m transition zone) from AGl to AGm is ob-served. L5 in area AGm was about 20% thicker than inarea AGl and took up about one-third (33%) of the totalthickness of this area. Areas AGl and AGm were of similarthickness (�2.0 mm) and were the thickest areas in therat cortex, being almost twice as thick as area Cg1. It isimportant to note, however, that the cortical thicknesschanged gradually from one cortical area to the next. Thisis quite unlike the lamination pattern, which exhibitedabrupt changes at areal boundaries. Another characteris-tic feature of area AGm was its strong myelinization (Fig.5B). In this respect, AGm compares with sensory areassuch as S1 and V1 but was very different from the muchmore weakly myelinated area AGl.

Staining for cytochrome C oxidase activity led to a rel-atively homogenous pattern in area AGm (Fig. 5C). Theoverall cytochrome C oxidase activity was lower than inS1, and the lamination pattern was less distinct than inS1. In the horizontal domain (parallel to the cortical sur-face), there was no indication of nonhomogeneties thatcould have corresponded to the representation of whiskerrows.

DISCUSSION

Cytoarchitectonics and motor maps in ratfrontal cortex

The data presented here suggest an excellent correspon-dence between cytoarchitectonic and physiological bound-aries in rat frontal cortex. Specifically, we find that areaAGm represents entirely and largely exclusively whiskermovements, area AGl represents paw movements (andpresumably also tail, trunk, neck, jaw, and tongue move-ments), posterior area Cg1 and area Cg3 represent eye

and periocular movements, and anterior area Cg1 repre-sents nose movements. Our observation that the boundarybetween area AGm and AGl corresponds to the physiolog-ical boundary between whisker and paw movementsagrees with the findings of Neafsey et al. (1986) but is atodds with the observations of Donoghue and Wise (1982).According to the data of Neafsey et al. (1986) the veryrostral parts of the rat cortex seem to contain a very smallfurther motor area with a more or less complete musclel-otopic body representation, which may represent the rat’ssecondary motor cortex (M2). The putative M2 cortex ismainly or completely situated in what is cytoarchitectoni-cally characterized as area AGm. The characteristics ofvibrissa movements evoked from this area are not clear;Neafsey and colleagues studied mainly limb movements.

Functional status of cytoarchitectonic andphysiological subdivisions

Area AGl is clearly a part of the rat primary motorcortex. This conclusion is supported by 1) low currentthresholds (generally �60 �A down to �10 �A) for move-ment initiation (Hall and Lindholm, 1974; Donoghue andWise, 1982; Gioanni and Lamarche, 1985; Neafsey et al.,1986; this study; data not shown); 2) its fine-grain internaltopography (Hall and Lindholm, 1974; Donoghue andWise, 1982; Gioanni and Lamarche, 1985; Neafsey et al.,1986; this study; data not shown); and 3) its topographicposition within the rat brain, where the motor represen-tation borders S1 cortex as a mirror image, an arrange-ment that is characteristic for M1 in many mammalianspecies (Creutzfeld, 1993).

The observations reported here strongly suggest thatarea AGm forms the vibrissa representation of rat pri-mary motor cortex. This conclusion is supported by 1)low current thresholds (generally �60 �A down to �10�A) for evoking whisker movements in area AGm (Halland Lindholm, 1974; Donoghue and Wise, 1982; Gioanniand Lamarche, 1985; Neafsey et al., 1986; this study); 2)the strictly topographic organization of AGm, as ob-served in our study; the fact that such an organizationwas not so clearly observed in other studies (Miyashitaet al., 1994) might have resulted from the use of per-pendicular penetrations in the curved AGm cortex; and3) the position of the AGm whisker representation in theoverall motor map of rat frontal cortex, where the facialrepresentation fits into the overall body map (see Fig. 5)to form a mirror image of S1. An alternative view of thestatus of area AGm advanced by Donoghue and Wise(1982), who, based mainly on the seemingly high stim-ulation thresholds in area AGm, proposed that it formsa higher order motor area. However, other studies haveobserved low stimulation thresholds in histologicallyverified penetrations in area AGm (Neafsey et al., 1986;Neafsey, 1990; this study) or at the stereotactic coordi-nates of area AGm (Hall and Lindholm, 1974; Gioanniand Lamarche, 1985; Huntley, 1997). Most of the puta-tively high-threshold/unresponsive sites that were re-ported for area AGm by Donoghue and Wise as well asother authors were described at very medial and ante-rior coordinates. At such locations, perpendicular dor-soventral penetrations for anatomical reasons do notreach the L5/L6 border, where stimulation thresholdare lowest in primary motor cortex. Thus, in thesecases, high stimulation thresholds might not have been

Fig. 6. Cell-based and penetration-based maps of motor cortex.Views of the rat motor cortex illustrated by surface projections of deeplayer stimulation maps. Left column: The cell-based partitioningscheme proposed here. Right column: A penetration-based mapadapted to the data of Hall and Lindholm (1974). In addition to M1, amap somatosensory cortex (S1) after Chapin and Lin (1984) and theM2 area (after Neafsey et al., 1986) are illustrated. Top: Dorsolateralview of the rat’s cerebral cortex with cell-based (left) and penetration-based (right) maps of M1. Colors in the left M1 map delineate bodyparts that are represented in different cytoarchitectonic regions. Mid-dle left: Coronal section through M1. Colors delineate different cyto-architectonic regions. Blue, area Cg1 (periocular, eye and nose move-ment motor cortex); green, area AGm (vibrissa motor cortex) and areaAGl (somatic motor cortex). Middle right: Coronal section through M1with a set of vertical penetrations and the respective motor responsesevoked in these penetrations. Bottom: Flattened surface maps of M1according to cell-based mapping (left) and penetration-based mapping(right). Scale bar � 500 �m.


intrinsic to area AGm but are probably best explained bya failure to stimulate the appropriate lamina.

A recent anatomical study (Hoffer et al., 2003) showedlabeling of putative vibrissa M1 after tracer injections inthe vibrissa barrel cortex. This study beautifully demon-strated that S1 inputs from vibrissa rows converge in ratvibrissa M1. As far as we can tell, the labeled M1 areacoincides well with area AGm as defined here, but theauthors refer to this area as area AGl and use unusualcoordinates both for area AGm and for area AGl (Hoffer etal., 2003). Anatomical work of Welker et al. (1988) in themouse identified a projection from barrel cortex to puta-tive motor cortex, which coincides well with our AGmcoordinates. Motor cortex organization in guinea pigs(Campos and Welker, 1976; Rapisarda et al., 1990) alsoseems to follow a pattern similar to what we have sug-gested here for the rat; such a conclusion is corroboratedby the cytoarchitectonic work of Rapisarda and colleagues(1990).

Neafsey and colleagues observed coactivation of vibrissaand eye movements in area AGm and have therefore pro-posed that area AGm may be comparable to the primatefrontal eye fields. However, studies that have thoroughlyexplored the medial and medial bank parts of rat frontalcortex have found that eye/periocular movements are rep-resented at distinct sites medial from the vibrissa repre-sentation (Hall and Lindholm, 1974; Sanes et al., 1990).Our study extends such findings by showing that eye/periocular movements are represented in cytoarchitec-tonically distinct area Cg1, and these finding rule out arole of AGm in oculomotor control.

Our finding that exclusively area AGm represents whis-ker movements is at odds with all partitioning schemesthat exclude area AGm from rat primary motor cortex.Such proposals imply that the rat would be the only mam-mal studied so far in which large parts of the face were notrepresented in M1.

The data presented here indicate that area Cg1 formsthe eye/periocular movement part of rat primary motorcortex. The idea that Cg1 belongs primary motor cortexis based on 1) the low current thresholds in Cg1 (gen-erally �60 �A down to �10 �A) for eye/periocular move-ments; 2) the topographically appropriate position ofthe Cg1 eye/periocular movement representation inthe overall M1 body map (Fig. 4); and 3) the largefraction of periocular movements compared with pureeye movements. Both the low stimulation thresholdsand the large fraction of periocular movements arecharacteristic of eye/periocular movement representa-tions in the primary motor cortex (Woolsey, 1958) andare different from higher order eye movement represen-tations such as the frontal eye fields (Bruce and Gold-berg, 1985).

As clearly indicated by the high stimulation thresh-olds, the minimal movements evoked, and the largenumber of unresponsive sites, area Cg3 is not part ofprimary motor cortex. This area does not contain arepresentation of the body muclelotopy but seems to beat least partially involved in oculomotor control. Assuggested by other authors (Gioanni an Lamarche,1985), the pupillary and eyelid-opening responsesevoked in areas Cg1 and Cg3 may be part of anautonomic/vegetative response pattern. The idea thatarea Cg3 is involved in the control of the autonomicnervous system is well supported by anatomical studies

(van der Kooy et al., 1982; Terreberry and Neafsey,1983; Vogt and Miller, 1983).

Cell-based vs. penetration-based maps of ratprimary motor cortex

Figure 6 (left column) illustrates a surface projectionof the deep layer motor map of rat primary motor cortexthat results from synopsis of the data on identified cells,ICMS experiments, and cytoarchitectonics. Accordingly,rat M1 is composed of at least three cytoarchitectonicareas (AGl, AGm, and Cg1) that together form a com-plete representation of the rat’s body surface. The novelaspect of this partitioning scheme is that it not only isbased on coordinates of stimulation sites but also takesinto account the relationship of the stimulated cells tothe cortical surface. We therefore refer to this mappingscheme as a cell-based motor map. This approach differsfrom previous mapping schemes, which considered thecoordinates of stimulation sites only from vertical pen-etrations and which we refer to as penetration-basedmaps (Fig. 6, right column). Such maps have been pub-lished by a number of authors (Hall and Lindholm,1974; Gioanni and Lamarche, 1985; Neafsey et al., 1986;Neafsey, 1990), and a surface map that has beenadapted according to the data of Hall and Lindholm(1974) is shown in Figure 6 (right column). Although thecell-based map and the penetration-based map are quitedifferent, a coronal view reveals that they may refer tothe entirely same neural substrate (Fig. 6, middle). Wealso included the putative M2 representation identifiedby Neafsey (1990) in our summary scheme.

As noted above, one weakness of penetration-basedmaps is that they are not consistent with cytoarchitec-tonic borders. Thus, according to the map of Hall andLindholm (1974), M1 ends in the middle of area AGm.

Another major functional difference between cell-based and penetration-based mapping becomes obviousif one considers flattened surface maps of the body rep-resentation (Fig. 6, bottom). Here it becomes clear thatpenetration-based mapping distorts the body represen-tation such that eye and whisker movements (that arerepresented in the curved parts of M1) become under-represented. Indeed, we argue that previous motormaps grossly underestimate the extent of vibrissa mo-tor cortex. Thus, we estimate that the vibrissa motorcortex has about 1.5-fold the surface area of the hind-and forelimb representation, whereas, in penetration-based mapping schemes, the vibrissa field is usuallysmaller than the hind- and forelimb representation(0.86-fold in the case of Gioanni and Lamarche, 1985).In this respect, cell-based mapping suggests that theproportion of the motor map may be more similar to thesomatosensory body map than previously thought (seeFig. 6, top row). In the S1 map, the hind-/forepaw bar-rels take up only one-third of the area of the large facialwhisker barrels of the posteromedial-barrel subfield(Riddle et al., 1992). The volumetric measurements ofWree et al. (1992) also demonstrate that the largest partof M1 tissue is accounted for by area AGm (16.2 mm3,44.5% of M1 volume), whereas areas AGl (14.5 mm3,39.8%) and Cg1 (5.7 mm3, 15.7%) constitute a muchsmaller volume of tissue.


Cytoarchitectonic specializations of areaAGm and whisking behavior

Area AGm is characterized by a very strong myeliniza-tion and an expanded L5. We argue that both these spe-cializations may be related to the control of whiskingbehavior. Rat whisking is a high-speed behavior, mediatedby a specialized musculature (Dorfl, 1982) consistingalmost entirely fast-contracting, quickly fatigable mus-cle fibers (Jin et al., 2004). Individual whisking sweepsrepeat at rates of 10 Hz or faster, and individual whisksreach speeds �3,000°/second (Welker, 1964; Carvell andSimons, 1990; Kleinfeld et al., 1999). Myelinization in-creases conduction velocity, and this may provide anadvantage in the control of this very fast behavior.Intracellular stimulation indicates that L5 neurons areinvolved in the temporal fine control of whisking. Spe-cifically, L5 stimulation evokes whisker movements of aconstant phase relative to the stimulation event fromone stimulation trial to the next (Brecht et al., 2004).Given the role of L5 in the temporal fine control ofwhisking behavior, we speculate that the expansion ofL5 in AGm may be an adaptation to the high speed ofwhisking behavior. This interpretation of cytoarchitec-tonic features of area AGm is in line with other recentevidence (Berg and Kleinfeld, 2003b) that implicates M1in the sweep by sweep control of whisking behavior.

ACKNOWLEDGMENTS

We thank Fritjof Helmchen, Ian Manns, and Jack Wa-ters for comments on the manuscript. Marlies Kaiser, RolfRodel, Peter Mayer, and Karl Schmidt provided excellenttechnical assistance. We are especially grateful for thehelp and advice of Marlies Kaiser and Petra Janson withvarious staining procedures.

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