Repeated ethanol exposure and withdrawal impairs human fear conditioning and depresses long-term potentiation in rat amygdala and hippocampus.

BACKGROUND: In rats, repeated episodes of alcohol consumption and withdrawal (RWD) impair fear conditioning to discrete cues. METHODS: Fear conditioning was measured in human binge drinkers as the increased startle response in the presence of a CS+ conditioned to aversive white noise. Secondly, the ability of tone CSs, paired with footshock, to induce c-fos expression, a marker of neuronal activity, in limbic structures subserving emotion was studied in rats. Additionally, consequences of RWD on subsequent induction of long term potentiation (LTP) in external capsule/lateral amygdala and Schaffer collateral/hippocampus CA1 pathways were studied in rat brain slices. RESULTS: Fear conditioning was impaired in young human binge drinkers. The ability of fear-conditioned CSs to increase c-fos expression in limbic brain areas was reduced following RWD, as was LTP induction. Rats conditioned prior to RWD, following RWD showed generalization of conditioned fear from the tone CS+ to a neutral control stimulus, and a novel tone. CONCLUSIONS: Binge-like drinking impairs fear conditioning, reduces LTP, and results in inappropriate generalization of learned fear responses. We propose a mechanism whereby RWD-induced synaptic plasticity reduces capacity for future learning, while allowing unconditioned stimuli access to neuronal pathways underlying conditioned fear.     

Individuals with Autism Spectrum Disorder Show Normal Responses to a Fear Potential Startle Paradigm

The present study utilized a fear potentiated startle paradigm to examine amygdala function in individuals with autism spectrum disorder. Two competing hypotheses regarding amygdala dysfunction in autism have been proposed: (1) The amygdala is under-responsive, in which case it would be predicted that, in a fear potentiated startle experiment, individuals with autism would exhibit decreased fear conditioning and/or potentiation, and (2) The amygdala is over responsive, in which case an exaggerated potentiation of the startle response would be predicted. Fourteen adolescents and adults diagnosed with autism spectrum disorder and 14 age, gender, IQ, and anxiety level-matched typical adolescents and adults participated. Both participants with autism and typical participants potentiated the startle response following fear conditioning and no group differences in the latency or amplitude of the potentiated startle response were found. These results suggest that this aspect of amygdala function, namely fear conditioning and potentiation of the startle response, is intact in individuals with autism.     

Activation of the amygdalo-entorhinal pathway in fear-conditioning in rat

Several studies implicate a role for the amygdala in processing of emotional memories that might partially occur in the connections between the amygdala and the hippocampal-parahippocampal areas. The present study was designed to determine if the pathway from the amygdala to the entorhinal cortex becomes activated during acquisition of fear-conditioning. First, the retrograde tracer Fluoro-Gold (FG) was iontophoresed into the entorhinal cortex in rats. Following habituation, animals were divided into five groups: (i) controls that received another habituation session; (ii) animals given a tone only; (iii) animals given a footshock only; (iv) animals given an unpaired presentation of a shock and a tone; and (v) conditioned animals that received a single tone-footshock pairing. Then double-immunohistochemistry against c-Fos and FG or glutamate decarboxylase (GAD67) was performed. The numbers and densities of labelled neurons were calculated in the lateral and basal nuclei of the amygdala. In conditioned animals the number and density of c-Fos-positive nuclei increased in dorsolateral and medial divisions of the lateral nucleus compared with the control group (P < 0.05). Additionally, in the medial division of the lateral nucleus, the percentage of c-Fos/FG double-labelled neurons was higher in the conditioned animals compared with the other groups (P < 0.05). Only a very few GAD67-positive interneurons expressed c-Fos. These data indicate that a part of the amygdalo-entorhinal pathway is activated during acquisition of fear-conditioning. These data support the idea that emotionally relevant sensory information in the lateral nucleus can influence information processing in the hippocampal and parahippocampal areas via the amygdalo-entorhinal pathway.     

Involvement of the human cerebellum in fear-conditioned potentiation of the acoustic startle response: a PET study

Fear-conditioned potentiation of the startle response was used to study the role of the cerebellum in associative learning of non-specific aversive reactions in healthy human subjects using PET. Prior PET scanning initially neutral light stimuli were paired with painful electric shocks (fear-conditioning phase). Four PET-scans each were performed with presentation of acoustic startle stimuli (T), fear-conditioned light stimuli (L) or acoustic stimuli paired with light (LT, potentation phase). As a measure of fear-conditioning subtraction of condition T from LT revealed an increase of regional cerebellar blood flow (rCBF) in the left cerebellar hemisphere. Subtraction of condition L from LT, as a measure of fear-conditioned potentiation, revealed an increase of rCBF in the medial cerebellum. Different parts of the cerebellum appear to be involved in this form of motor associative learning.     

Clonidine injections into the lateral nucleus of the amygdala block acquisition and expression of fear-potentiated startle

Numerous studies of aversive learning with different animal models have shown that the noradrenergic system has an important role in the acquisition, consolidation and expression of aversive learning. We used intracerebral clonidine injections to investigate the role of the noradrenergic amygdaloid system in the fear-potentiated startle paradigm. Clonidine is a noradrenergic alpha2-receptor agonist which can decrease noradrenergic transmission by stimulating presynaptic alpha2-receptors. Rats received injections of 0, 2.5, 5 and 10 nmol clonidine into the lateral amygdala (i) before fear-conditioning, (ii) immediately after fear-conditioning, (iii) before testing and (iv) before both fear-conditioning and the testing of conditioned fear. Clonidine injections blocked the acquisition and expression of conditioned fear. The effect on acquisition was not caused by state-dependency or possible side-effects of clonidine on consolidation. Given that clonidine decreases amygdaloid noradrenaline release, these results show a crucial role of noradrenergic transmission within the amygdala in classical fear-conditioning. Surprisingly, both the acquisition and the expression of conditioned fear were blocked after amygdaloid injections of clonidine, suggesting that amygdaloid noradrenaline is necessary to induce both unconditioned and conditioned fear.     

Fear conditioning in virtual reality contexts: a new tool for the study of anxiety.

BACKGROUND: Context conditioning has been suggested to model clinical anxiety, but context, as manipulated in animal models, has not been translated to human studies. A virtual environment might prove to be the ideal tool for innovative experimental paradigms to study explicitly cued fear and contextual anxiety in humans. METHODS: Subjects were guided through a virtual environment that consisted of two rooms connected by a street scene. In each of the rooms, a blue and a yellow panel on a wall served as explicit conditioned stimuli (CS). The panels were displayed several times. One of the panels (CS+) was associated with a shock in one of the rooms (shock room). No shock was administered in the other room (safe room). Acoustic startle stimuli were administered in the presence and in the absence of the panels to assess explicit cued conditioning to the CS and context conditioning to the rooms, respectively. RESULTS: Startle was potentiated by the CS+ in both rooms, which suggests generalization of fear across contexts. After acquisition, startle was potentiated in the shock room, compared with the safe room, in the absence of the CS+. CONCLUSIONS: These results support the future use of virtual reality to design new conditioning experiments to study both fear and anxiety.     

Metabotropic glutamate receptors are involved in amygdaloid plasticity

The amygdala plays an important role in emotional learning. Synaptic plasticity underlying the acquisition of conditioned fear occurs in the lateral nucleus of the amygdala: long-term potentiation (LTP) of synapses in the pathway of the conditioned stimulus (CS) has shown to be a neural correlate of this kind of emotional learning. The present study is based on previous results of our laboratory showing an important role of the metabotropic glutamate receptor subtype 5 (mGluR5) in fear conditioning. Here, we explored whether mGlu5 receptors within the lateral nucleus of the amygdala are involved in the plasticity underlying fear conditioning. We used an in vivo approach investigating the acquisition, consolidation and expression of conditioned fear by the fear-potentiated startle paradigm and by the inhibition of motor activity during CS presentation. Additionally, we used an in vitro approach inducing LTP in the lateral amygdala by patch-clamp recordings in rat brain slices. Acquisition of conditioned fear, but not consolidation and expression, was blocked by intra-amygdaloid injections of the specific mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) in vivo. Furthermore, induction of amygdaloid LTP but not synaptic transmission was disrupted by MPEP application in vitro. These experiments show for the first time in vivo and in vitro that mGluR5 receptors are necessary for plasticity in the amygdala.     

Induction and transient suppression of long-term potentiation in the peri- and postrhinal cortices following theta-related stimulation of hippocampal field CA1

During behavioral events associated with periods of likely mnemonic processing, CA1 pyramidal cells in rats typically discharge repetitively in either high-frequency bursts (`complex spikes') or single spikes, both of which are tightly phase-locked to the hippocampal theta rhythm. Interestingly, patterned stimulation which mimics the repetitive, learning-related complex spike discharges are optimal for inducing long-term potentiation (LTP) of excitatory field potentials in CA1, and patterned stimulation which mimics the theta-related single action potentials results in a robust and lasting depotentiation at these same synapses. The aim of the present study was to determine the extent to which these physiologically-relevant patterns of hippocampal stimulation have similar effects on synaptic efficacy in the monosynaptic projection from CA1 to the perirhinal and postrhinal cortices (PRh), areas thought to play a prominent role in many forms of learning and memory. Single-pulse stimulation of CA1 evoked a small amplitude, short latency population excitatory postsynaptic potential (EPSP) in the PRh. Theta-burst stimulation (TBS; n=8) delivered to CA1 reliably potentiated the PRh EPSP slope for at least 30 min. Theta-pulse stimulation (TPS; 5 Hz; n=4) delivered to CA1 5 min after TBS substantially but transiently suppressed EPSP slope relative to that of potentiated control preparations. Collectively these data suggest that theta-related patterns of hippocampal activation can reliably induce and transiently suppress LTP in PRh, and are consistent with the notion that behaviorally-relevant, theta-modulated patterns of CA1 unit activity may result in both long- and short-term alterations of synaptic strength within their rhinal cortical targets.     

Vertex-recorded, rather than primary somatosensory cortex-recorded, somatosensory-evoked potentials signal unpleasantness of noxious stimuli in the rat

In the present study, we investigated in the rat whether vertex- or primary somatosensory cortex-recorded somatosensory-evoked potentials (Vx-SEP/SI-SEP, respectively) signal unpleasantness of noxious stimuli. Therefore, initially we characterised fentanyl effects (0, 20, 40 or 50 microg/kg/h) on somatosensory and auditory processing by recording Vx-/SI-SEPs and vertex- and primary auditory cortex-recorded auditory-evoked potentials (Vx-/AI-AEPs, respectively). Subsequently, in a separate experiment, the animals were subjected to a Pavlovian fear-conditioning paradigm. The noxious stimuli applied to evoke Vx-/SI-SEPs (unconditioned stimulus (US)) were paired to a tone (conditioned stimulus (CS)) under 'steady state' conditions of 0, 20, 40 or 50 microg/kg/h fentanyl. Vx-/SI-SEPs were recorded simultaneously during these trials. After CS-US presentation, CS-induced fear-conditioned behaviour was analysed in relation to the SEPs recorded during CS-US presentation and the AEPs recorded in the first experiment. While the SI-SEP and AI-AEP were minimally but significantly affected, fentanyl dose-dependently decreased the Vx-SEP and Vx-AEP. The decrease of the Vx-SEP and Vx-AEP was parallelled by the dose-dependent decrease of the amount of CS-induced fear-conditioned behaviour. These results suggest that the dose-dependent decrease of the Vx-SEP amplitude, rather than of the SI-SEP, indicates that the US was experienced as less unpleasant. Next to an altered US processing, altered CS processing contributed to the decrease of the amount of CS-induced fear-conditioned behaviour as indicated by the dose-dependent decrease of the Vx-AEP.     

Opposite effects of tetanic stimulation of the auditory thalamus or auditory cortex on the acoustic startle reflex in awake rats

The amygdala mediates both emotional learning and fear potentiation of startle. The lateral amygdala nucleus (LA) receives auditory inputs from both the auditory thalamus (medial geniculate nucleus; MGN) and auditory association cortex (AAC), and is critical for auditory fear conditioning. The central amygdala nucleus, which has intra-amygdaloid connections with LA, enhances startle magnitude via midbrain connections to the startle circuits. Tetanic stimulation of either MGN or AAC in vitro or in vivo can induce long-term potentiation in LA. In the present study, behavioural consequences of tetanization of these auditory afferents were investigated in awake rats. The acoustic startle reflex of rats was enhanced by tetanic stimulation of MGN, but suppressed by that of AAC. All the tetanization-induced changes of startle diminished within 24 h. Blockade of GABAB receptors in the LA area reversed the suppressive effect of tetanic stimulation of AAC on startle but did not change the enhancing effect of tetanic stimulation of MGN. Moreover, transient electrical stimulation of MGN enhanced the acoustic startle reflex when it lagged behind acoustic stimulation, but inhibited the acoustic startle reflex when it preceded acoustic stimulation. The results of the present study indicate that MGN and AAC afferents to LA play different roles in emotional modulation of startle, and AAC afferents are more influenced by inhibitory GABAB transmission in LA.     

The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle.

BACKGROUND: The startle reflex is potentiated by aversive states. It has been proposed that phasic startle potentiation to a threat cue and sustained startle potentiation to contextual stimuli reflect distinct processes mediated by different brain structures. The present study tested the hypothesis that alprazolam would reduce the sustained startle potentiation to contextual threats but not the startle potentiation to a threat cue. METHODS: Sixteen healthy subjects received each of four treatments: placebo, .5 mg of alprazolam, 1 mg of alprazolam, and 50 mg of diphenhydramine (Benadryl) in a crossover design. Participants were exposed to three conditions, including one in which predictable aversive shocks were signaled by a cue, a second in which shocks were administered unpredictably, and a third condition in which no shocks were anticipated. Acoustic startle were delivered regularly across conditions. RESULTS: Phasic startle potentiation to the threat cue in the predictable condition was not affected by alprazolam. In contrast, the sustained increase in startle in the predictable and unpredictable conditions was reduced significantly by the high dose of alprazolam. CONCLUSIONS: Startle responses to an explicit threat cue and to an aversive context are psychopharmacologically distinct, suggesting that they may represent functionally dissociable aversive states.     

Opposing roles of the amygdala and dorsolateral periaqueductal gray in fear-potentiated startle

The whole-body acoustic startle response is a short-latency reflex mediated by a relatively simple neural circuit in the lower brainstem and spinal cord. The amplitude of this reflex is markedly enhanced by moderate fear levels, and less effectively increased by higher fear levels. Extensive evidence indicates that the amygdala plays a key role in the potentiation of startle by moderate fear. More recent evidence suggests that the periaqueductal gray is involved in the loss of potentiated startle at higher levels of fear. The influence of both structures may be mediated by anatomical connections with the acoustic startle circuit, perhaps at the level of the nucleus reticularis pontis caudalis. The mediated by anatomical connections with the acoustic startle circuit, perhaps at the level of the nucleus reticularis pontis caudalis. The present chapter reviews these data.     

Context conditioning and behavioral avoidance in a virtual reality environment: effect of predictability.

BACKGROUND: Sustained anxiety can be modeled using context conditioning, which can be studied in a virtual reality environment. Unpredictable stressors increase context conditioning in animals. This study examined context conditioning to predictable and unpredictable shocks in humans using behavioral avoidance, potentiated startle, and subjective reports of anxiety. METHODS: Subjects were guided through three virtual rooms (no-shock, predictable, unpredictable contexts). Eight-sec duration colored lights served as conditioned stimuli (CS). During acquisition, no shock was administered in the no-shock context. Shocks were paired with the CS in the predictable context and were administered randomly in the unpredictable context. No shock was administered during extinction. Startle stimuli were delivered during CS and between CS to assess cued and context conditioning, respectively. To assess avoidance, subjects freely navigated into two of the three contexts to retrieve money. RESULTS: Startle between CS was potentiated in the unpredictable context compared to the two other contexts. Following acquisition, subjects showed a strong preference for the no-shock context and avoidance of the unpredictable context. CONCLUSIONS: Consistent with animal data, context conditioning is increased by unpredictability. These data support virtual reality as a tool to extend research on physiological and behavioral signs of fear and anxiety in humans.     

Direct connection between perirhinal cortex and hippocampus is a major constituent of the lateral perforant path

Single-pulse stimulation of the perirhinal cortex (PRC) evoked field responses in the dorsal hippocampal CA1 region in urethane-anesthetized rats. In depth profiles conducted by moving the PRC stimulating electrode, the largest amplitude hippocampal potential was generated when the stimulating electrode was located within the perirhinal region. More dorsal (temporal cortex) or more ventral (lateral entorhinal cortex) stimulating sites elicited minimal hippocampal potentials. The hippocampal response was maintained during 100 Hz stimulation of the PRC, suggesting that it was monosynaptic, and high-frequency stimulation (400 Hz) of the PRC produced a significant potentiation of hippocampal CA1 field potentials (46.73 ± 4.14%). When the PRC and the lateral perforant path (LPP) were stimulated separately, the depth/amplitude profiles obtained from a roving recording electrode located within the dorsal hippocampus were similar. In order to determine if fibers from PRC project to the hippocampus via the LPP, the PRC-CA1 and LPP-CA1 potentials were recorded prior to and during procaine (20%, 0.5 μl) blockade of the LPP. A simultaneous loss of both potentials was observed immediately following procaine infusion, while a commissural control potential was unaffected. Both LPP and PRC potentials returned approximately 30–40 min later. Electrolytic lesions of PRC produced a significant decrease in the amplitude of LPP-hippocampal potentials when testing was conducted 4–5 days postlesion. Lesions of lateral entorhinal cortex or temporal cortex did not produce such effects. These data suggest that a direct pathway from perirhinal cortex to the dorsal hippocampal CA1 field can undergo long-term potentiation (LTP) and that this pathway makes a major contribution to the lateral perforant path. © 1996 Wiley-Liss, Inc.     

Alpha2-adrenoreceptor activation inhibits LTP and LTD in the basolateral amygdala: involvement of Gi/o-protein-mediated modulation of Ca2+-channels and inwardly rectifying K+-channels in LTD

Activation of adrenoreceptors modulates synaptic transmission in the basolateral amygdala. Here, we investigated the effects of alpha2-adrenoreceptor activation on long-term depression and long-term potentiation in an in vitro slice preparation of the mouse basolateral amygdala. Field potentials and excitatory postsynaptic currents were evoked in the basolateral amygdala by stimulating the lateral amygdala. Norepinephrine (20 micro m) reduced synaptic transmission and completely blocked the induction of long-term potentiation and long-term depression. The alpha2-adrenoreceptor antagonist yohimbine (2 micro m) reversed this effect. The alpha2-adrenoreceptor agonist clonidine (10 micro m) mimicked the effects of norepinephrine. The Gi/o-protein inhibitor pertussis toxin (5 micro g/mL) reversed the effect of clonidine. Long-term depression was blocked in the presence of omega-conotoxin GVIA, but not omega-agatoxin IVA. Clonidine inhibited voltage-activated Ca2+ currents mediated via N- or P/Q-type Ca2+-channels. The inhibitory action of clonidine on long-term depression was reversed when inwardly rectifying K+-channels were blocked by Ba2+ (300 micro m). The present data suggest that alpha2-adrenoreceptor activation impairs the induction of long-term depression in the basolateral amygdala by a Gi/o-protein-mediated inhibition of presynaptic N-type Ca2+-channels and activation of inwardly-rectifying K+-channels.     

Lesions of the nucleus basalis magnocellularis do not impair prepulse inhibition and latent inhibition of fear-potentiated startle in the rat

The present study tested if lesions of the nucleus basalis magnocellularis (NBM) affect prepulse inhibition (PPI) of the acoustic startle response and latent inhibition (LI) of fear-potentiated startle. The NBM is known to play an important role in learning and memory. Recently, the interest of research focused on its role in attentional and response selection processes. We here tested the effect of excitotoxic NBM-lesions on PPI, a phenomenon of sensorimotor gating that occurs at early stages of information processing. We also assessed the lesion effects on LI, a phenomenon of reduced conditioning after stimulus preexposure that can be used to measure selective attention. Bilateral infusions into the NBM of 80 nmol of quinolinic acid markedly reduced the number of choline acetyltransferase immunopositive neurons in the NBM and lead to a pronounced reduction of acetylcholine esterase in the cortex and the amygdala. However, no effects on PPI, fear-conditioning, or LI of fear-potentiated startle were found. Therefore, we conclude that there is no NBM-driven attentional or response selection process involved in PPI. Furthermore, the simple association learning in the classical conditioning paradigm used for fear-potentiated startle or LI is unaffected by NBM-lesions.     

Neural plasticity and stress induced changes in defense in the rat

We investigated the effects of predator stress on behavior and amygdala afferent and efferent neural transmission in rats. Pathways studied were: ventral angular bundle input to the basolateral amygdala; central and basolateral amygdala output to the periaqueductal gray (PAG). Predator stress was ‘anxiogenic’ in elevated plus maze, light/dark box and acoustic startle tests one week after stress. Lasting changes were also observed in neural transmission. Predator stress appeared to potentiate right and depotentiate left hemisphere afferent amygdala transmission. In contrast, predator stress potentiated amygdala efferent transmission to right and left PAG, depending on the amygdala nucleus stimulated. Paired pulse and intensity series analysis suggests that transmission changes may be postsynaptic or presynaptic, depending on the pathway. Path analysis relating brain and behavioral changes suggests that potentiation and depotentiation in both hemispheres participate jointly in effecting some, but not all, of the behavioral changes produced by predator stress. Potentiation in left hemisphere amygdala afferents and efferents predicts anxiolytic-like effects, while potentiation in the right hemisphere amygdala afferents predicts anxiogenic-like effects. Path analysis also supports the view that changes in different neural systems mediate changes in different behaviors. These findings have their parallel in studies in the cat, but there are species differences.     

Hippocampal pathway to the amygdala and stress ulcer development

The objective of the first study was to localize the reported aggravation of stress ulcers found after large bilateral hippocampal lesions in rats. Lesions in the ventral hippocampus produced a similar increase in the severity of gastric erosions after cold-restraint, as was seen after large bilateral lesions. Dorsal hippocampal damage produced no differential effects. In the second experiment, high-frequency electrical stimulation of the ventral CA1 region of the hippocampus, a procedure known to induce long-term potentiation, increased the evoked potentials in the lateral central nucleus of the amygdala, and in adjacent parts of the lateral and basolateral nuclei. The increase in the efficacy of synaptic transmission in this pathway attenuated stress ulcer development. It was concluded that the ventral hippocampus is part of a coping system, and a strengthening of synaptic connections with the central amygdala increases the coping ability of rats under stress conditions.     

The effects of sex and neonatal maternal separation on fear-potentiated and light-enhanced startle

This study was based on the higher prevalence of anxiety disorders in women than in men, and on the finding that early adverse experiences are a major risk factor for the development of anxiety disorders later in life. The object of this study was to investigate in rats, the sensitivities of the light-enhanced startle (LES) and fear-potentiated startle (FPS) paradigms to sex differences and to determine the effects of maternal separation (MS) on the baseline startle magnitude and potentiated startle response in these paradigms. Pups in the MS group were separated daily from their mother for 180 min/day from postnatal day 2 (PND2) to PND14. Control litters remained undisturbed. The adult male and female progeny were tested in the FPS and LES. As predicted, females showed a significantly greater potentiation of startle than males in the FPS, and a strong trend towards greater startle potentiation in the LES. Contrary to predictions, MS had no effect on startle potentiation in the FPS and severely disrupted LES in female, but not male rats. The observed sex differences add to the validity of the FPS and LES as animal paradigms of fear and anxiety. The findings indicate that these paradigms can be used to study the biological basis of sex differences in fear and anxiety. In contrast, the effects of MS on startle potentiation argue against the idea that MS provides a robust model for the predicted influences of early adverse effects on these startle potentiation measures of fear and anxiety.     

Increase in [3H]glutamate release from slices of dentate gyrus and hippocampus following classical conditioning in the rat

The release of amino acids was examined in three hippocampal areas following classical conditioning. Paired or unpaired tone(CS)-shock(US) presentations were given to animals engaged in a previously acquired food-motivated lever-pressing task. Conditioned suppression of lever-pressing was the behavioural measure of conditioning. The dentate gyrus and areas CA1 and CA3 of the hippocampus were removed bilaterally from conditioned and pseudoconditioned animals, and slices cut and stored in liquid nitrogen for subsequent in vitro analysis of the release of radiolabelled glutamate and aspartate. K+-stimulated release of radiolabelled amino acids was analysed in the presence and absence of extracellular Ca2+. Potassium-stimulated, Ca2+-dependent release of [3H]glutamate was significantly greater in slices of dentate gyrus and area CA1 prepared from conditioned animals than from pseudoconditioned animals. This finding identifies a neurochemical change associated with classical conditioning which is similar to the increase in transmitter release seen in hippocampal long-term potentiation (LTP), and which is consistent with the hypothesis that an LTP-like mechanism is involved in mnemonic processes.