it is located at the interface of these two vastly different environments , and thus is charged with making the final decision about what , from an uncontrolled and often hostile chemical surround , should be incorporated into the highly controlled biochemical environment within .
taste is the beginning of a long chemosensory tube that extends from palate to intestines , with receptors along that length that are sensitive to the products liberated by digestion .
those on the palate are not unique to taste ; the same receptors often occur elsewhere in the body . what is unique is that those serving taste gather their information before the irrevocable decision to swallow has been made , and so can influence that decision .
hence , whereas the distribution of information from other chemical sensors may be limited to the gastrointestinal ( gi ) tract , or may be conveyed through the vagus only to the hindbrain , that from taste receptors is projected through the brainstem to the thalamus and multiple cortical sites as well as to ventral forebrain areas .
this vast distribution through the central nervous system permits the control of somatic and autonomic reflexes , a cognitive evaluation , and hedonic appreciation .
an apt metaphor for taste is a janus head , mounted on an ancient city gate , one face turned outward to assess the traffic beyond the walls , warning of approaching toxins and alerting gatekeepers to the availability of nutrients ; the other turned inward to monitor the city 's changing needs and to adjust its decisions of what passes through the city walls to satisfy them ( scott , 1987 ) .
this view of the role of gustation as a visceral ( internal ) as well as somatic ( external ) sense defines its learning capacity .
taste is exquisitely well suited to learn from visceral consequences ( satiety , nausea ) ; it is less inclined to learn from those that are somatic ( tones , lights , and shocks ) . as garcia noted in describing the development of a taste aversion following a meal , no other aspect of the event
was implicated in having caused nausea : not his dinner companions , the table settings , or the background music , only the visceral component represented by the taste of the meal ( garcia et al . , 1985 ) .
the realm of conditioning can be broadly divided into those events that one can do something about , and those that one can not .
the former typically demands operant conditioning to manipulate the environment to one 's satisfaction , using somatic senses to gather information and striated muscles for action ; the latter more commonly demands classical conditioning to prepare for the inevitable , often using smooth muscles .
gustatory learning serves as a special case of classical conditioning , with taste representing the conditioned stimulus ( cs ) , and the visceral sequelae of ingestion , the unconditioned stimulus ( us ) .
it has been proposed that the visceral response alters the reward value of the taste , and that this new value then guides the animal 's behavior to either seek or avoid that taste ( rolls , 2005 ) .
such learning can occur in an appetitive or aversive direction , with the establishment of either conditioned taste aversions ( ctas ) or preferences ( ctps ) .
it is of greater urgency to the animal to avoid a chemical that has sickened it than to develop a preference for one among many that have proven to provide nutrition .
the cta is readily established with a single pairing of the gustatory cs and the visceral us , even with a cs - us interval for several hours .
it is not impaired by placing the animal under deep anesthesia or rendering it comatose before the us is delivered .
indeed , the predisposition of an animal to develop a cta is so striking that the investigators first suspected it to be an artifact , a suspicion laid to rest only by an exhaustive series of studies and arguments ( revusky , 1977 ) .
as easily as it is created , a cta is notoriously difficult to extinguish ( nolan et al . , 1997 ) .
the cta also has a robust impact on behavior , often suppressing subsequent acceptance of the cs to less than 10% of preconditioned levels , even in animals motivated to consume by moderate deprivation .
with such a dramatic impact on behavior , the cta has a half - century history as a rich topic of research .
thousands of studies were conducted during the 1960s and 1970s on behavioral variables such as the distinctiveness and novelty of the taste , the nature and severity of the nausea , the amount of time between them and how that time was spent . with these clearly defined , the cta could be employed by researchers as a tool for altering taste acceptability , creating a profound reduction in acceptance of the cs , from which generalization gradients of both quality and intensity could be determined to reveal the relative similarities among taste qualities . in parallel
, behavioral neuroscientists began to investigate the mechanisms by which this extraordinary learning process occurred , using rats in nearly all studies .
they performed lesions of taste pathways and relays to determine which areas of the nervous system were required in order to develop and retain a cta .
there followed electrophysiological investigations of the impact of a cta on taste processing , immunohistochemical studies of gene expression elicited by a cta , and microdialysis experiments on the neurochemical consequences of the experience .
a ctp can be established rather quickly by pairing a novel taste with recovery from a dietary deficiency , most notably the provision of thiamine to animals on a thiamine - deficient diet ( rodgers , 1967 ; capretta , 1977 ) .
more commonly , however , the impact of a ctp on behavior is revealed only gradually over days of continuous pairing of taste with nutrition , though that impact can reach levels equal to those of a cta in the opposite direction , i.e. , approaching 100% preference ( sclafani and nissenbaum , 1988 ) .
the electrophysiological and neurochemical concomitants of a ctp are also more subtle than those of a cta . yet
, the ctp may have played a larger role in defining human culture than the cta , for while the latter is powerful , it is idiosyncratic to the individual .
the ctp , by contrast , is often shared by members of a culture where certain foods are available .
it is typical of a culture 's cuisine that there are a few piquant tastes ( the cs ) accompanied by carbohydrate loads ( the us ) .
the gustatory cs comes to be favored by association with the nutritional us , and the cuisine , with all its cultural trappings and traditions , tends to bind its consumers together as part of their cultural identity . in the paragraphs that follow , i will review some of the work on the mechanisms of ctas and ctps that have come from our laboratory and those of our colleagues .
the ingredients of the cta  taste and visceral distress  are represented widely across the cns .
investigators have performed lesions of areas that receive such inputs in an effort to define which are crucial to the creation and to subsequent retention of a cta .
results implicate the area postrema in acquisition ( rabin et al . , 1983a ) , but not retention ( rabin et al . , 1983b )
they reveal that loss of the parabrachial nuclei ( pbn ) causes the most profound disruption on both creating a cta ( with lesions of the lateral division ) ( spector et al . , 1992 ;
yamamoto et al . , 1994 ) and maintaining a previous aversion ( medial division ) ( sakai et al . , 1994 ) .
they implicate the ventromedial globus pallidus in both acquisition and retention ( hernadi et al . , 1997 ) .
electrolytic lesions of the basolateral amygdala disrupt the creation and retention of a cta ( yamamoto et al . , 1995 ) , but nmda lesions , which spare fibers of passage , do not ( chambers , 1990 ) ; thus the amygdala remains a likely participant in cta formation , but the axons that pass through it may be of greater import , since leaving them intact sustains the learning .
lesions of prefrontal cortex have yielded conflicting results , and its role in ctas remains uncertain .
those in insular cortex ( ic ) , however , reliably degrade cta acquisition ( braun et al .
, 1982 ; bermudez - rattoni and mcgaugh , 1991 ) and have an even larger impact on retention
. thus , the cast of participants in creating and retaining a cta as demonstrated by these fixed , permanent lesions range from the deepest recesses of the brain stem through ventral forebrain to the neocortex .
greater insight may be gleaned from lesions that are reversible , or that combine the loss of more than one area .
ivanova and bures ( 1990a , b ) temporarily disabled regions of the brainstem with microinjections of tetrodotoxin ( ttx ) .
they reported that ttx injected in the pbn up to one day in advance or four days following training blocked the consolidation of a cta without affecting the rejection threshold for quinine .
thus , taste processing per se remained intact , but the associative functions required for learning the aversion were disrupted by inactivation of the pbn
. the crucial role of pbn in mediating associative taste learning was reinforced by clark and bernstein ( 2009 ) .
these investigators performed asymmetrical , unilateral lesions of the pbn and ic , and thereby disrupted cta acquisition .
however , when both lesions were made in the same hemisphere , leaving the contralateral hemisphere intact , learning proceeded normally .
the effect of a cta is to reverse the behavioral reaction to a previously preferred taste to one of the revulsion .
the rejection response is organized in caudal brainstem ( norgren and grill , 1982 ) and released in stereotypical fashion upon encountering an inherently aversive stimulus or one to which a cta has been formed .
the nucleus of the solitary tract ( nst ) , the first central relay for taste , is likely to be involved in cta formation . here
gustatory and visceral afferents converge ( norgren , 1981 ) yet do not directly overlap , communicating instead via the adjacent reticular formation , offering a close association between signals from the two necessary components of a cta .
chang and scott ( 1984 ) took single neuron recordings from the nst of rats that were ( 1 ) unconditioned ( tasted the saccharin cs with no subsequent nausea ) , ( 2 ) pseudoconditioned ( experienced the nausea us with no preceding taste ) , or ( 3 ) conditioned ( the taste of the saccharin cs was paired with licl - induced nausea us ) .
the recordings revealed that sweet - oriented nst neurons gave exaggerated responses to the saccharin cs in conditioned rats , and that the increase was due to a sharp spike of activity that peaked at about 900 msec following stimulus delivery ( figure 1 ) .
moreover , the neural response profile to saccharin in conditioned rats was more similar to those of aversive stimuli .
we concluded that the sensory code for the saccharin cs ( and , to a lesser extent , for other sweet stimuli ) was altered at the first central taste relay by conditioning , and that such a modification could explain not only the behavioral reaction , but also the immunohistochemical , and neurochemical consequences of a cta described below .
such a modification of the taste signal might also reveal why the cephalic phase insulin release from the pancreas , a parasympathetic reflex elicited by sweet taste , is blocked after a cta has been created to that taste ( louis - sylvestre and lemagnen , 1980 ) .
the altered neural message would lose the capacity to innervate the vagal efferents responsible for stimulating pancreatic  cells .
post - stimulus time histograms of the mean responses among sweet - sensitive neurons in the nucleus of the solitary tract to the conditioned stimulus : 0.0025 m sodium saccharin .
activity is shown for control ( dotted line ) , pseudoconditioned ( dashed line ) , and conditioned ( solid line ) rats .
the enhanced activity during the first three seconds of the evoked response in conditioned animals may represent the increased salience of the sodium saccharin taste and its aversive quality . in a subsequent experiment , we created , and then fully extinguished a cta to saccharin ( nolan et al . , 1997 ) , then recorded responses to saccharin and other stimuli in these recovered rats and in unconditioned controls ( mccaughey et al . , 1997 ) .
the mean responses to all stimuli were no different in the two groups of rats , nor was there any significant difference between the neural response profiles to any taste .
however , the neural activity was not completely restored to the preconditioning state . there remained a clear vestige of the conditioning experience in an attenuated burst given to the cs by the sweet - sensitive subgroup of neurons .
the burst was no longer associated with conditioned behavior  which was fully extinguished  though it may have served as a permanent marker for a once - salient cs that can abet subsequent reacquisition of the aversion .
curiously , lesions in gustatory nst do not interfere with either the acquisition or retention of a cta ( grigson et al .
, 1997 ; shimura et al . , 1997a ) . even if the electrophysiological effects recounted above were only advisory to a more commanding cta nucleus or circuit , the blockade of taste information at this obligatory synapse would appear to prevent any subsequent learning .
the lack of an impact may reflect the inadequacy of lesions to fully compromise a functioning relay , particularly when they must spare adjacent areas that control vital reflexes , including respiration . in the parabrachial nucleus ,
the creation of a cta to nacl resulted in an elevated response to that stimulus in sodium - specific taste cells , in agreement with the responses to the saccharin cs in the nst described above ( shimura et al . , 1997b ) .
the same was found in the ic ( yamamoto et al . , 1989 ) and amygdala , where an exaggerated response to the cs is often expressed as inhibition ( yasoshima et al . , 1995 ) .
finally , in the hypothalamus of nave rats , the taste of saccharin activates areas associated with feeding and inhibits those for satiety ; after the saccharin is paired with nausea , these roles are reversed ( aleksanyan et al . , 1976 ) .
thus , the impact of a cta is demonstrable in the electrophysiological activity of neurons across the widely dispersed regions that process taste activity , and that impact is appropriate to guide the aversive reaction to the cs that follows conditioning .
the formation of long - term memories requires the expression of immediate early genes and the synthesis of their associated proteins ( mcgaugh , 2000 ) .
the gene c - fos has been shown to be expressed and the associated fos protein synthesized in a variety of species as a basis for modifying the neural activity associated with learning ( sanyal et al . , 2002 ) .
c - fos expression , then , can serve as a useful index of conditioning .
1994 ) demonstrated that sucrose elicited c - fos expression in the nst after it had been paired with an intraperitoneal injection of licl .
this was not simply a response to the aversive taste that sucrose had become , for quinine did not induce the same expression in unconditioned rats ( houpt et al . , 1996 ) .
however , this index of learning in nst was blocked when the amygdala was impaired , demonstrating the importance of centrifugal fibers in mediating the conditioning process ( schafe and bernstein , 1996 ) .
his colleagues have shown that c - fos is induced in cells in the medial division of pbn by hedonically positive tastes associated with ingestion , and in neurons in more lateral divisions by aversive tastes .
saccharin activates medial cells in nave rats , but after the saccharin has been paired with a licl injection , its taste induced c - fos expression in the lateral division ( yamamoto et al . , 1994 ) .
moreover , when c - fos expression was blocked in pbn , cta learning was impaired , just as it is when the pbn is lesioned ( yasoshima et al . , 2006 ) .
thus , a functioning pbn , capable of modifying its responses to a taste stimulus as a consequence of experience , is crucial to learning to avoid toxins . in forebrain , bernstein and koh ( 2007 )
addressed the issue of which areas reacted to novel tastes differently from those that were familiar , since only the former serve as effective conditioned stimuli .
they used c - fos expression to identify the central nucleus of the amygdala ( cna ) and ic as two such sites .
the next question was which of these also responded to the us , the second of the necessary elements of a cta .
only the cna expressed c - fos to a licl us , implicating this nucleus as a crucial nexus for making the association . yet while ic , which had responded to gustatory novelty , did not show increased c - fos expression to the us alone , its neurons did respond to pairing of the cs and us , reinforcing its role in the associative process , perhaps through communication with the pbn and amygdala ( ferreira et al . , 2006 ) .
gene expression , of course , is a precursor of protein production , and it is assumed that the protein is the basis for forming the associative memory .
accordingly , when protein synthesis was inhibited by administration of anisomycin into the ic , a cta was not formed ( rosenblum et al . , 1993 ) .
more specifically , the administration of oligodeoxynucleotide ( odn ) antisense to c - fos in the amygdala blocked cta acquisition ( lamprecht and dudai , 1996 ) .
again , the two critical forebrain regions  ic and amygdala  are implicated , and the capacity of their neurons to synthesize proteins in general , and fos in particular , is essential to associative learning . finally , bernstein and her colleagues ( barot et al . , 2008 ;
used a direct visualization approach to identify neurons that responded both to the cs and us , reasoning that this afforded them prima facie data from which to support the association .
they found such cells only in the basolateral nucleus of the amygdala , and only under normal training conditions , i.e. , cs followed by us .
the bulk of evidence from gene expression studies , then , focuses on three structures as being central to the acquisition and retention of ctas : the pbn , the amygdala ( both central and basolateral nuclei ) , and the ic .
it is unsurprising , then , that when the cs to which a cta has been developed is subsequently presented , reminiscent of that experience , plasma corticosteroid levels rise ( smotherman et al . , 1976 ) .
yet , the cta does not depend on this adrenal index of stress , for adrenalectomized rats acquired ctas as readily as controls ( ader et al . , 1978 ) .
a more specific measure of the impact of a cta is seen in the levels of neurochemicals associated with reward or aversion , particularly in the limbic system .
reward is associated with increased dopamine ( hoebel , 1984 ) and reduced acetylcholine ( rada et al . ,
1991 ) in the nucleus accumbens , and lowered serotonin levels in the paraventricular hypothalamus ( stanley et al . , 1989 ) . this relationship has been demonstrated both through microdialysis , where dopamine levels in the accumbens rose following a sweet taste , and conversely through reverse microdialysis in which dopamine administered to the accumbens increased sucrose consumption ( hajnal and norgren , 2001 ) .
the taste of saccharin evoked dopamine release in the rat 's accumbens , in accord with its reinforcing value .
however , if the saccharin had been paired with nausea to create a cta , the same stimulus caused a reduction in dopamine , and instead a release of acetylcholine in accumbens ( mark et al .
, 1991 ) , and serotonin in the hypothalamus ( west et al . , 1991 ) , denying the neurochemical basis for reward .
when subjects develop a cta , there is little doubt that they are subsequently repulsed by the taste .
not only do they avoid it , they also show the well - defined mimetic reflexes of aversiveness : gaping , head - shaking , and chin - rubbing .
all that follows  the blockade of parasympathetic reflexes , the alteration of the afferent signal and its projection to brain areas associated with avoidance , the reversal of neurochemical release from rewarding to aversive  is in accord with this powerful experience .
the behavior changes only over days of training , though the cs does finally reach asymptotically high levels of acceptance , and is quite resistant to extinction .
mimetic responses of rats , however , do not change as the cs wins acceptance , raising the question of whether the hedonic quality of the cs has increased ( sclafani , 1991 ) .
( 1997 ) recorded electrophysiological responses from the nst of rats that had been conditioned to prefer either of two formerly aversive chemicals . in each case , the gustatory code was modified to reflect a less aversive quality , though the effect was less pronounced than that seen in the opposite direction upon creation of a cta ( chang and scott , 1984 ) .
secondly , the taste for which a preference was acquired now elicited a heightened dopamine release in the nucleus accumbens , a clear neurochemical marker of reward ( mark et al . , 1994 ) .
the animal knows two facts : what the chemical was ( taste ) , and what it did ( gi ) .
this information permits it to tailor its chemical selection to full individual advantage over a lifetime .
the learning process draws on responses that extend from the viscera through caudal brainstem , to ventral forebrain and cortex , implying an ancient system , much like the control of feeding itself .
it is only a marginally conscious process , for ctas can be learned while comatose , and most people can not recall the occasion upon which they developed a food aversion ( bernstein , 1985 ) . conditioned aversions and preferences provide the operative link between the chemical and biochemical environments .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
 taste is the final arbiter of which chemicals from the environment will be admitted to the body . 
 the action of swallowing a substance leads to a physiological consequence of which the taste system should be informed . 
 accordingly , taste neurons in the central nervous system are closely allied with those that receive input from the viscera so as to monitor the impact of a recently ingested substance . 
 there is behavioral , anatomical , electrophysiological , gene expression , and neurochemical evidence that the consequences of ingestion influence subsequent food selection through development of either a conditioned taste aversion ( cta ) ( if illness ensues ) or a conditioned taste preference ( ctp ) ( if nutrition ) . 
 this ongoing communication between taste and the viscera permits the animal to tailor its taste system to its individual needs over a lifetime . 
Introduction
Conditioned taste aversion: Lesion studies
Conditioned taste aversion: Electrophysiology
Conditioned taste aversion: Gene expression
Conditioned taste aversion: Neurochemistry
Conditioned taste preference
Conclusion
Conflict of interest statement