Physiological Psychology1976, Vol. 4 (3),275-280

Short-latency discriminative unit response:Engram or bias?

MICHAEL GABRIELUniversity of Texas at Austin, Austin, Texas 78712

Recent studies have shown changes during conditioning in CS-related neuronal activity. Thechanges were associative in character, similar to behavioral changes which result from conditioning.However, unlike behavioral conditioned responses, the neuronal responses had very short latencies(5-35 msec). In the present paper, two hypotheses accounting for the short-latency associative activityare examined. One hypothesis assumes acquisition of a neuronal modification (engram) in the vicinityof the recording electrode. The second hypothesis postulates a tonic flow of impulses originating froma distant neural locus, which biases the activity of the recorded neurons to produce the associativeresponse. Implications of each viewpoint are examined and the greater appeal of the bias hypothesisis asserted, based upon certain implausible implications of the engram hypothesis. Recently obtaineddata are presented which favor the bias hypothesis over the engram hypothesis for one CNS locality.

In recent years there has been great interest in thestudy of neuronal correlates (single and multiple­unit) of learning in awake behaving animals (seereviews of John, 1967; Kandel & Spencer, 1968;Leiman & Christian, 1973; Thompson, Patterson, &Teyler, 1972). This article is concerned with oneparticular finding from some of these studies. It isthe observation of associative (learned) responsesdisplayed by CNS neurons to stimuli used as CSs forconditioning, An example is the data of Olds andhis colleagues (Kornblith & aids, 1973; aids,Disterhoft, Segal, Kornblith, & Hirsh, 1972) forneurons of various CNS regions in the rat, and byGabriel and his colleagues (Gabriel, Miller, &Saltwick, 1976, in press; Gabriel, Satlwick, & Miller,1975; Gabriel, Wheeler, & Thompson, 1973a, b) forneurons of the rabbit anterior cingulate corticalregion and the rabbit medial geniculate nucleus . Inthese studies, neuronal activity showed the associa­tive characteristic of stimulus control, i.e., greaterfrequency of firing to the CS used for con­ditioning compared to stimuli not paired with rein­forcement. These studies had appropriate controlsto eliminate nonassociative interpretations of thedata. 1 Most importantly, the studies showed that theneuronal effect occurs with very short latency(5-35 msec) measured from stimulus onset.

Here, our interest is with a particular interpre­tation of such findings, specifically, the one pre­sented by Olds et al. (1972). Their interpretation

The author wishes to thank Dr. Dennis McFadden for in­sights and critical comments essential to the manuscript. Theresearch results presented in this paper were supported bygrants from the Biomedical Sciences Committee, the SpencerFoundation, and by National Institute of Mental Health GrantMH 26276-01.

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is stated with considerable precision, so that a numberof implications become immediately evident withregard to the nature and direction of future researchon the neurophysiological basis of learning. However,implications are only as valid as their generativeassumptions. The purpose of the present paper isto show that the initial assumptions of Olds et al.(1972) are not necessary or compelling regarding thesignificance of short-latency associative neuronalreactions. An alternative set of assumptions andsupporting data will be provided, and the alternativeimplications for future research, spelled out.

Olds and his co-workers asserted that the neuronallatencies observed in their study were so short thatthere was not sufficient time for synaptic trans­mission or conduction over appreciable distanceswithin the CNS. Therefore, short-latency associativeresponses to the CS could not first occur at a CNSlocus distant from the locus of recording, only laterto arrive at the locus of recording. Rather, they mustbe direct effects of the stimulus, totally uninfluencedby stimulus-evoked inputs relayed from other partsof the brain.

Since there is insufficient time for a neural influenceto be relayed from a great distance, such an influencecannot account for the short-latency activity of theneuron. It follows that the responding neuronmust contain within itself, or very near to itself, amechanism sufficient to mediate the associativeresponse. The mechanism is a localized structuralor metabolic change of neurons acquired duringconditioning, It may be identified as a member ofone of the classes denoted by the concept, "engram."Thus, by the theory under consideration, an engramunderlying the neuronal activity must exist in a loca­tion which is within or very close to the recordedneuron, and the neuronal activity functions to indicate

~ 76 GABRIEL

the locus of the engram. In the words of Olds andhis co-workers, the neuronal activity is "at the siteof the mnemonic record" (Olds et al., 1972).

The phrase, "engram hypothesis," will be usedin the remainder of this paper to denote this inter­pretation . A primary implication of the engramhypothesis is that one may "map" the neuro­anatomical loci of engrams in the brain by notingall points which display a short-latency associativeeffect. Ultimately, this argument paves the way fora powerful approach to the study of neuroanatomicalspecificity in learning.

The precise nature of the molecular mechanismwhereby engrams are formed is not at issue here.Many models have been proposed to explain theirformation (e.g., Burke, 1966; Pfaff, 1969). Theseare all equivalent for purposes of the present dis­cussion, in that they all postulate local changes inthe CNS to result from interactions during condition­ing among a small number (2-5) of cells. What isat issue is the validity of the idea that engrams in­variably underlie short-latency neuronal reactions.

The engram hypothesis fosters an optimistic out­look on the potential fruitfulness of mapping theCNS for learning-related structural change. Thusone may easily wish that the hypothesis were true.Unfortunately, certain considerations show thatcaution is called for in interpreting short-latencyresponses solely in terms of the engram hypothesis.The latter viewpoint is not the only one able toaccount for such responses. Moreover, the engramview has implications which lead to implausible pre­dictions. These do not seem likely to receive empiricalsupport.

Of crucial importance to the engram hypothesisis the fact that there is insufficient time for short­latency responses to be affected by prior neuronalevents in the interval beginning at CS onset. Thus, acentral premise of the engram hypothesis is thatshort-latency responses are not relayed from distantregions which previously responded to the CS. Thispremise seems an essentially sound one. However,the engram hypothesis uses this premise to asserta corollary proposition which is not sound. It is theidea that short-latency responses occur without anyinfluence from distant regions of the CNS. · Fromthis, it follows that one may "map" the CNS forlocalized engrams by noting points which yield short­latency responses. Moreover, the corollary proposi­tion implies that short-latency responses occur tothe absolute, not relative, properties of the incomingstimulus.'

A major problem with the corollary propositionand its implications is that they are inconsistent withthe well-established principle that stimulus controlof a learned response is exerted by the context ofthe learning situation, as well as by specific response-

signaling cues. This point may be illustrated in avariety of ways. For example, postconditioningexposure of subjects to the conditioning apparatus,in the absence of the CS, produced complete extinc­tion of behavioral CRs (Gabriel, 1970; Gabriel &Vogt, 1972). If contextual stimuli exert control overlearned behavioral responses, why then should notcontextual stimuli also influence conditioned neuronalresponses? It seems reasonable to assume that themechanisms which mediate short-latency neuronalreactions are context-dependent mechanisms. Assuch, they would take on different properties in eachsituation encountered by an organism. Contextualstimuli affect severai sensory modalities. Thus, theproperties appropriate to a given context wouldbe signaled to a given CNS locality via several sensorypathways, and inputs from several regions of thebrain would govern short-latency reactions. Thealternative assumption, that engrams dedicate neuronsto exclusive control by specific isolated stimuli, isunpalatable at best. It seems remote indeed that ashort-latency conditioned neuronal response wouldoccur to the absolute properties of a discrete CSoutside of the environment in which conditioningtook place. Yet this represents one of the experi ­mental results which would be required to providepreferential support of the engram hypothesis.

The problems referred to are consequent upon theadopt ion of the engram hypothesis. The purpose ofthe present paper is to point out that there existsan alternative to the engram hypothesis . Thealternative hypothesis, like the engram hypothesis,accounts for associative reactions with short latency.Yet, the alternative view is preferable because itavoids the implausible features of the engramhypothesis.

Assume that some neurons are tonically influencedto respond to some inputs and not to others. Inother words, assume that some neurons are con­tinuously bombarded by synaptic inputs, and thatthese inputs bias the neurons to respond to signifi­cant stimuli, and to "ignore" nonsignificant stimuli .

Bias may be assumed to operate upon singleneurons, but it need not originate within or nearbythem. Instead, it may be carried to a given neuronover a considerable distance along a path which isseparate from the one bearing information aboutthe stimulus. The centrifugal pathways whichmediate neural modulatory effects at relativelyperipheral levels of certain sensory systems (e.g.,Granit, 1955; Winter, 1965) represent examples ofanatomical organization appropriate to i Q~ biashypothesis.

The idea of bias is a relatively general one; It IS

represented by a variety of specific hypotheticalmechanisms. One example is the selective filteringmechanism believed by some investigators (e.g.,

Hernandez-Peon, Scherrer, & Jouvet, 1956) tooperate upon neural transmission in afferent path­ways, and to underlie the behavioral phenomena ofselective attention.

On the other hand, a more general notion thanbias, which subsumes the latter, is the idea of "set,"or the totality of sustained responses to contextualstimuli (e.g., apparatus stimuli) of a learning situa­tion. It is instructive to consider bias as a sub­mechanism of set, because in so doing, one ap­preciates the sustained effects of bias. That is, biasexists tonically in a sustained fashion before, during,and after the presentation of a discrete signal (e.g.,CS). Just as a filtered electronic circuit, a neuralconduction pathway with bias remains biasedwhether or not a signal is present. Clearly the spiritof the bias hypothesis is compatible with the well­demonstrated controlling effects of contextual cuesupon conditioned responses.

It is important to note that the involvement ofthe concept of set does not mean that the short­latency neuronal responses are not learned responses.Insofar as they conform to the criteria of associativelearning, they are just as legitimately associative incharacter as behavioral conditioned responses.Moreover, set itself is a learned effect assumed tobe conditioned to and evoked by contextual stimuliof the learning situation.

An important consequence of the bias hypothesisis that one is disinclined to use short-latency acquiredunit responses to "map" the neuroanatomical lociof structural (learning) changes. This is true becausethe tonic bias mediating an associative neuronalresponse may originate at a CNS locus distant fromthe locus of the responding neuron. Thus, the locusof the latter need not be the same as the locus ofan engram.

One question which should be raised is the questionof whether there are any reasons other than theoreticalones favoring the bias hypothesis over the engramhypothesis. Recall the centrifugal neuroanatomicalpathways which mediate modulation of afferentneural activity. These pathways support the biashypothesis in that they illustrate possible. anatomicalbases of the biasing mechanism, but they do notcompel acceptance of the hypothesis. To demon­strate bias, one must first show neural activity in abehaving subject which is unequivocally associativein nature. In addition, one must demonstrate that theassociative neuronal activity is dependent upon the in­fluence of some (presumably centrifugal) conductionpathway other than the afferent path to the re­sponding neuron. Unfortunately for the bias hypo­thesis, the second of these two effects has not beendemonstrated.

Recent observations from our own laboratory do

SHORT.LATENCY UNIT RESPONSE 277

not meet all of the requirements for a demonstra­tion of biasing, but they do provide a posteriorisupport of the bias hypothesis over the engramhypothesis (Gabriel, Miller & Saltwick, 1976; Gabriel,Saltwick, & Miller, 1975). In these studies, we ob­served differential conditioning and reversal of shortlatency multiple-unit activity in the medial geniculatenucleus (MGN) of the rabbit. These changes occurredin parallel with acquisition and reversal of a dis­criminative behavioral (avoidance) CR.

The observation of reversal of the acquiredneuronal response eliminated possible nonassocia­tive interpretations of the data. Moreover, our effectappeared to be a prime candidate for explanationby the bias hypothesis. This is true because of therapid switching seen on early sessions of reversaltraining between the neuronal response appropriateto acquisition and that appropriate to reversal(Figure I). Specifically, either abrupt loss or reversalof the discriminative neuronal activity appropriateto original acquisition occurred in the initial sessionsof reversal training. Speaking anthropomorphically,these abrupt neuronal changes suggested that thesubjects quickly switched off or reversed the listeningstrategy of acquisition, in response to the occurrenceof extra shocks received on the early sessions ofreversal. Since the subjects adopted the safe strategyof responding behaviorally to both CS + and CS­on subsequent sessions, relatively few shocks occurredon these sessions and the listening strategy (MGNneuronal response) reverted in some subjects to thedominant one used in the previous (acquisition)task . Only after considerable additional experiencewith the reversal task, were both behavioral andneuronal (attentional?) reversal achieved. Thecritical point is that it seems more reasonable toaccount for the sudden switches of the differentialneuronal response in terms of a rapid switching ofthe pattern of centrifugal flow into MGN than interms of a rapid manufacture, dissolution, and re­manufacture of structures (engrams) within MGN.The return during reversal training of the MGNresponse appropriate to the acquisition task isespecially difficult for the engram hypothesis, sincethe latter must account for reformation of an "old"engram in the presence of differential reinforce­ment appropriate to the opposite ("new") engram.The centrifugal flow assumed by the bias hypothesisto account for these effects may have occurred overone of the recently documented corticofugal projec­tions to MGN (Pontes, Reis, & Sousa-Pinto, 1975;Watanabe, Yanagisawa, Kanzaki, & Katsuki, 1966).

The reader may argue that the bias hypothesis lacksparsimony. It pushes the problem of structural changeoff to some remote and unspecified region of the eNS.Moreover, the kind of structural changes required in

278 GABRIEL

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Figure I. The graphs shown here illustrate the relationships between neuronal (MGN) and behavioral response during differentialconditioning (left or vertical lines) and reversal (right of vertical lines) in three rabbits. The lower portion of each graph shows thepercentage of behavioral responses to the CS+ and the CS- over consecutive daily sessions. The CS+ was either an 8·kHz tone (e) ora I-kHz tone (0). The upper portions of the graph show the magnitude of the MGN differential response [CS+ (acquisition) - CS­(acquisition)] in each session. The scores were based on the IO-msec period (bin) after CS onset, which showed the greatest cross­over in terminal reversal relative to terminal acquisition. The same bin was used throughout the analysis of a given subject's data. Bins5, 5, and 6 were used for rabbits 41, 42, 45, respectively . Virtually identical results were obtained when the average value of five binssurrounding the single bin shown here were used. Each bar shows the magnitude of the differential response (CS+ - CS-) minus themagnitude of this difference obtained during pretraining with tones plus noncontingent shock . Bars above the baseline in acquisitionreflect a greater response to the acquisition CS+ than to the acquisition CS-. Bars below the baseline in reversal indicate a greaterresponse to the reversal CS+ than to the reversal CS-. These data illustrate abrupt crossover just after the onset of reversal training,followed by a return to the response appropriate to acquisition training, and a change back to the reversal pattern, at the end .Further details of these results are presented by Gabriel, Miller, and Saltwick (1976).

these remote regions would have to be very complex in­deed if they are to account for the switchingof listeningstrategieswhichwas suggestedby our data .

Fortunately for the bias hypothesis, these argu­ments are not compelling . The ability to switchlistening strategies is in allliklihood an ability whichis analogous to, say, locomotion or digital control.One could assume that considerable neural circuitryfor these abilities is prewired, that the learning re­quired to actualize this circuitry takes place early indevelopment, and that control over listening strategyis well overlearned in the adult. The problem facinga subject in conditioning is thus not that of learningfrom scratch to produce a listening strategy, butrather, that of learning which of many possible well­practiced strategies to adopt in a given situation.The signaling of an appropriate prewired listeningstrategy would be considerably less complex thande novo learning of the strategy. It is also compatiblewith the abrupt switching of MGN filtering whichis suggested by our results to occur in the initialsessions of reversal training.

This argument simplifies the informational "load"placed upon structural engrams. Nevertheless, it isclear that some structural change is necessary toaccomplish the relatively simple signaling of ap­propriate listening strategies. It is tempting to specu­late that structural changes (engrams) account ex­clusively for the ability of contextual stimuli to elicitappropriate sensory and motor biases, and that thebiases, in turn, account exclusively for short-latencyassociative reactions .

Clearly, the bias hypothesis argues against theidea of mapping the brain for short-latency neuronalresponses in order to localize engrams. However,the implications of bias are not uniformly negativewith respect to possible electrophysiological analysesof neuroanatomical factors in learning . Rather, thebias hypothesis causes a shift in emphasis away fromlocalization of engrams toward a search for the CNSsystems which mediate tonic biasing effects . Speci­fically, the bias hypothesis fosters a search for neuralsystems which show a tonic associative response tocontextual properties of the learning situation, whichhave neuroanatomical projections to the regionsmanifesting short-latency associative reactions, andwhich can be shown to bear a necessary relation­ship to the short-latency responses.

This analysis stresses the importance of tonicassociative activity in the CNS. Thus, one may raisea question regarding the usefulness of research whichfocuses on phasic short-latency neuronal responses .If these cannot be used to localize engrams, thenwhat good are they? In fact, the study of short-latencyeffects is an essential component of electrophysio­logical analyses of brain function relevant to condi­tioning.

SHORT-LATENCYUNIT RESPONSE 279

As Olds has pointed out, short-latency reactionsare not relayed from other brain regions, or fromincipient effector activity. Thus they yield a pictureof activity specific to the recorded locus not con­founded by inputs from more quickly respondingregions. In the absence of mediation from otherregions, tonic bias or local engram would seem themajor feasible alternatives remaining to account forshort-latency responses ." Thus, the discovery of sitesyielding short-latency responses sets the stage forsubsequent analyses. The subsequent analyses mayestablish the origins of tonic bias. If exhaustive searchfails. to reveal tonic effects, this would suggest thatlocal engrams account for the short-latency response,and microbiophysical analyses may reveal theengrams.

A second point should be made with respect tothe usefulness of short-latency reactions. Becausethese reactions are not relayed from distant loci,they should be expected to yield information aboutthe function of neural transmission at the recordedloci. Results of recent studies have supported thisexpectation by showing distinctive neuron-behaviorrelationships in different brain regions. For example,the short-latency response of neurons of rabbit limbiccortex and anterior thalamus shows acquisition ofan original discrimination, increased magnitudeof the original discrimination on the initial sessionsof reversal training, and no clear reversal effect atthe end of reversal training (Gabriel, Miller, &Saltwick, in press). This outcome is to be contrastedwith the discriminative activity of MGN, as reportedabove. The MGN showed abrupt equalization orreversal of the original discrimination at the onset ofreversal training, and a clear reversal effect at theend of reversal training.

A detailed discussion of these findings is con­tained in the original reports. For the present purpose,it is sufficient to point out the unique relationshipto behavioral performance shown by the neuronalactivity in different regions of the CNS. Theimplication is that each region contributed uniquelyto behavioral output. Thus, it would appear thatshort-latency reactions provide information on thedistinctive behavioral relevance of activity in differentparts of the brain.

One final point. It is necessary to mention thatOlds and his colleagues have recognized the biashypothesis, and have attributed importance to it(e.g., Disterhof & Olds, 1972; Kornblith & Olds,1973) relative to the position which they espousedin Olds et al., (1972). Only the latter article placesvirtually exclusive emphasis on the engram argument.The purpose of the present paper is not to criticizetheir obviously excellent work but primarily toindicate that the loci of engrams may not be identifiedwith loci yielding short-latency associative responses.

280 GABRIEL

REFERENCE NOTE

I. Olds, J . Presentation given at the workshop on neural organi­zation/or/earning. Winter Conference for Brain Research. January1976. Keystone . Colorado.

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NOTES

I. Recently, Olds has reported the possib ilit y that a cycl icfactor related to the regular occurrence of reinforcement mayhave contributed to the short-latency reactions in his studi es .Thus the claim that they were cue-speci fic associative reactionswas called into question. However, cue-specific short-latencyneuronal responses were demonstrated in some brain regionseven when the cyclic factor was eliminated (Olds, Note I).

2. The corollary proposition is not explicitly stated by Oldsand his colleagues (Olds et al., 1972). However , it is full y implicitin their contention that one may map for localized engrams bynoting the points wh ich yield short-latency responses.

3. There is a thi rd alternative able to account for the sho rt­latency rea ctions. This alternative is essentiall y a combina tion ofthe tonic bias hypothesis and the engram hypothesis. It stat esthat local engrams account for short-latency reactions, but inorder to do so the eng rams must be activated by a tonic inputother than the a fferent input to the recorded neuron. Thus manydifferent engrams exist in a given locality (sa y, MGN), bu t adistinctive tonic input is necessary for a particular subset ofthese to exert an effect on neuronal activity . Detailed co nsidera­tion of this possibility was not given in the present paper becauseit has less parsimony than the tonic bias and local engram hypo­theses , and because the combination hypothesis seems difficultto rationalize in terms of established principles of cellular neuronalinteraction . Moreover, the combina tio n hypothesis calls for thesame experimental approach as that called for by the tonic bia shypothesis.

(Received for publication December I , 1975;revision accepted March 3, 1976. )