Showing papers on "Classical conditioning published in 2011"

Altered processing of contextual information during fear extinction in PTSD: an fMRI study.

Abstract: Medial prefrontal cortical areas have been hypothesized to underlie altered contextual processing in posttraumatic stress disorder (PTSD). We investigated brain signaling of contextual information in this disorder. Eighteen PTSD subjects and 16 healthy trauma-exposed subjects underwent a two-day fear conditioning and extinction paradigm. On day 1, within visual context A, a conditioned stimulus (CS) was followed 60% of the time by an electric shock (conditioning). The conditioned response was then extinguished (extinction learning) in context B. On day 2, recall of the extinction memory was tested in context B. Skin conductance response (SCR) and functional magnetic resonance imaging (fMRI) data were collected during context presentations. There were no SCR group differences in any context presentation. Concerning fMRI data, during late conditioning, when context A signaled danger, PTSD subjects showed dorsal anterior cingulate cortical (dACC) hyperactivation. During early extinction, when context B had not yet fully acquired signal value for safety, PTSD subjects still showed dACC hyperactivation. During late extinction, when context B had come to signal safety, they showed ventromedial prefrontal cortex (vmPFC) hypoactivation. During early extinction recall, when context B signaled safety, they showed both vmPFC hypoactivation and dACC hyperactivation. These findings suggest that PTSD subjects show alterations in the processing of contextual information related to danger and safety. This impairment is manifest even prior to a physiologically-measured, cue-elicited fear response, and characterized by hypoactivation in vmPFC and hyperactivation in dACC.

Central amygdala activity during fear conditioning.

Abstract: The central amygdala (Ce), particularly its medial sector (CeM), is the main output station of the amygdala for conditioned fear responses. However, there is uncertainty regarding the nature of CeM control over conditioned fear. The present study aimed to clarify this question using unit recordings in rats. Fear conditioning caused most CeM neurons to increase their conditioned stimulus (CS) responsiveness. The next day, CeM cells responded similarly during the recall test, but these responses disappeared as extinction of conditioned fear progressed. In contrast, the CS elicited no significant average change in central lateral (CeL) firing rates during fear conditioning and a small but significant reduction during the recall test. Yet, cell-by-cell analyses disclosed large but heterogeneous CS-evoked responses in CeL. By the end of fear conditioning, roughly equal proportions of CeL cells exhibited excitatory (CeL+) or inhibitory (CeL−) CS-evoked responses (∼10%). The next day, the proportion of CeL− cells tripled with no change in the incidence of CeL+ cells, suggesting that conditioning leads to overnight synaptic plasticity in an inhibitory input to CeL− cells. As in CeM, extinction training caused the disappearance of CS-evoked activity in CeL. Overall, these findings suggest that conditioned freezing depends on increased CeM responses to the CS. The large increase in the incidence of CeL− but not CeL+ cells from conditioning to recall leads us to propose a model of fear conditioning involving the potentiation of an extrinsic inhibitory input (from the amygdala or elsewhere) to CeL, ultimately leading to disinhibition of CeM neurons.

Neural circuitry and plasticity mechanisms underlying delay eyeblink conditioning.

Abstract: Pavlovian eyeblink conditioning has been used extensively as a model system for examining the neural mechanisms underlying associative learning. Delay eyeblink conditioning depends on the intermediate cerebellum ipsilateral to the conditioned eye. Evidence favors a two-site plasticity model within the cerebellum with long-term depression of parallel fiber synapses on Purkinje cells and long-term potentiation of mossy fiber synapses on neurons in the anterior interpositus nucleus. Conditioned stimulus and unconditioned stimulus inputs arise from the pontine nuclei and inferior olive, respectively, converging in the cerebellar cortex and deep nuclei. Projections from subcortical sensory nuclei to the pontine nuclei that are necessary for eyeblink conditioning are beginning to be identified, and recent studies indicate that there are dynamic interactions between sensory thalamic nuclei and the cerebellum during eyeblink conditioning. Cerebellar output is projected to the magnocellular red nucleus and then to the motor nuclei that generate the blink response(s). Tremendous progress has been made toward determining the neural mechanisms of delay eyeblink conditioning but there are still significant gaps in our understanding of the necessary neural circuitry and plasticity mechanisms underlying cerebellar learning.

The acquisition of fear of movement-related pain and associative learning: a novel pain-relevant human fear conditioning paradigm

Abstract: Current fear-avoidance models consider fear of pain as a key factor in the development of chronic musculoskeletal pain. Generally, the idea is that by virtue of the formation of associations or acquired propositional knowledge about the relation between neutral movements and pain, these movements may signal pain, and hence start to elicit defensive fear responses (eg, avoidance behavior). This assumption has never been investigated experimentally. Therefore, we developed a pain-relevant fear conditioning paradigm using a movement as a conditioned stimulus (CS) and a painful electrocutaneous stimulus as an unconditioned stimulus (US) to examine the acquisition of fear of movement-related pain in healthy subjects. In a within-subjects design, participants manipulated a joystick to the left/right in the experimental (predictable) condition, and upward/downward in the control (unpredictable) condition or vice versa. In the predictable condition, one movement direction (CS+), and not the other (CS-), was followed by painful stimuli. In the unpredictable condition, painful stimuli were always delivered during the intertrial interval. Both fear of movement-related pain ratings and eyeblink startle measures were more elevated in response to the CS+ than to the CS-, whereas no differences occurred between both unreinforced CSs in the control condition. Participants were slower initiating a CS+ movement than a CS- movement, while response latencies to CSs in the control condition did not differ. These data support the acquisition of fear of movement-related pain by associative learning. Results are discussed in the broader context of the acquisition of pain-related fear in patients with musculoskeletal pain.

Cerebellar-Dependent Learning in Larval Zebrafish

Abstract: Understanding how neuronal network activity contributes to memory formation is challenged by the complexity of most brain circuits and the restricted ability to monitor the activity of neuronal populations in vivo. The developing zebrafish (Danio rerio) is an animal model that circumvents these problems, because zebrafish larvae possess a rich behavioral repertoire and an accessible brain. Here, we developed a classical conditioning paradigm in which 6- to 8-d-old larvae develop an enhanced motor response to a visual stimulus (conditioned stimulus, CS) when it is paired with touch (unconditioned stimulus, US). Using in vivo calcium imaging we demonstrate that CS and US activate different subsets of neurons in the cerebellum; their activity, modulated by learning two-photon laser ablation, revealed that the cerebellum is involved in acquisition and extinction, but not the retention, of this memory.

Exploring prefrontal cortical memory mechanisms with eyeblink conditioning.

Abstract: Several studies in nonhuman primates have shown that neurons in the dorsolateral prefrontal cortex have activity that persists throughout the delay period in delayed matching to sample tasks, and age-related changes in the microcolumnar organization of the prefrontal cortex are significantly correlated with age-related declines in cognition. Activity that persists beyond the presentation of a stimulus could mediate working memory processes, and disruption of those processes could account for memory deficits that often accompany the aging process. These potential memory and aging mechanisms are being systematically examined with eyeblink conditioning paradigms in nonprimate mammalian animal models including the rabbit. The trace version of the conditioning paradigm is a particularly good system to explore declarative memory since humans do not acquire trace conditioning if they are unable to become cognitively aware of the association between a conditioning tone and an airpuff to the eye. This conditioning paradigm has been used to show that the hippocampus and cerebellum interact functionally since both conditioned responses and conditioned hippocampal pyramidal neuron activity are abolished following lesions of the cerebellar nuclei and since hippocampal lesions prevent or abolish trace conditioned blinks. However, because there are no direct connections between the hippocampal formation and the cerebellum, and because the hippocampus is not necessary for trace conditioning after a period of consolidation has elapsed, we and others have been examining the prefrontal cortex for its role in forebrain-dependent trace eyeblink conditioning. This review examines some of the literature which suggests that the prefrontal cortex serves to orchestrate a neuronal network that interacts with the cerebellum to mediate adaptively timed conditioned responses.

Age sensitivity of behavioral tests and brain substrates of normal aging in mice.

Abstract: Knowledge of age sensitivity, the capacity of a behavioral test to reliably detect age-related changes, has utility in the design of experiments to elucidate processes of normal aging. We review the application of these tests in studies of normal aging and compare and contrast the age sensitivity of the Barnes maze, eyeblink classical conditioning, fear conditioning, Morris water maze, and rotorod. These tests have all been implemented to assess normal age-related changes in learning and memory in rodents, which generalize in many cases to age-related changes in learning and memory in all mammals, including humans. Behavioral assessments are a valuable means to measure functional outcomes of neuroscientific studies of aging. Highlighted in this review are the attributes and limitations of these measures in mice in the context of age sensitivity and processes of brain aging. Attributes of these tests include reliability and validity as assessments of learning and memory, well-defined neural substrates, and sensitivity to neural and pharmacological manipulations and disruptions. These tests engage the hippocampus and/or the cerebellum, two structures centrally involved in learning and memory that undergo functional and anatomical changes in normal aging. A test that is less well represented in studies of normal aging, the context pre-exposure facilitation effect (CPFE) in fear conditioning, is described as a method to increase sensitivity of contextual fear conditioning to changes in the hippocampus. Recommendations for increasing the age sensitivity of all measures of normal aging in mice are included, as well as a discussion of the potential of the under-studied CPFE to advance understanding of subtle hippocampus-mediated phenomena.

Multiple memory traces after associative learning in the honey bee antennal lobe

Abstract: We investigated the effect of associative learning on early sensory processing, by combining classical conditioning with in vivo calcium-imaging of secondary olfactory neurons, the projection neurons (PNs) in the honey bee antennal lobe (AL). We trained bees in a differential conditioning paradigm in which one odour (A+) was paired with a reward, while another odour (B-) was presented without a reward. Two to five hours after differential conditioning, the two odour-response patterns became more different in bees that learned to discriminate between A and B, but not in bees that did not discriminate. This learning-related change in neural odour representations can be traced back to glomerulus-specific neural plasticity, which depended on the response profile of the glomerulus before training. (i) Glomeruli responding to A but not to B generally increased in response strength. (ii) Glomeruli responding to B but not to A did not change in response strength. (iii) Glomeruli responding to A and B decreased in response strength. (iv) Glomeruli not responding to A or B increased in response strength. The data are consistent with a neural network model of the AL, which we based on two plastic synapse types and two well-known learning rules: associative, reinforcer-dependent Hebbian plasticity at synapses between olfactory receptor neurons (ORNs) and PNs; and reinforcer-independent Hebbian plasticity at synapses between local interneurons and ORNs. The observed changes strengthen the idea that odour learning optimizes odour representations, and facilitates the detection and discrimination of learned odours.

Impaired delay and trace eyeblink conditioning in school-age children with fetal alcohol syndrome

Abstract: Descriptive studies spanning three decades have identified a broad range of cognitive and behavioral deficits in children with fetal alcohol spectrum disorder (FASD) FASD ranges from fetal alcohol syndrome (FAS), which is the most severe impairment characterized by a distinctive craniofacial dysmorphology, small head circumference, and pre- and/or postnatal growth retardation, to alcohol-related neurodevelopmental disorder (ARND), in which children exhibit significant cognitive and behavioral impairment but lack the distinctive facial anomalies (Hoyme et al, 2005) The long-term adverse effects associated with fetal alcohol exposure are increasingly well known, but many women continue to drink heavily during pregnancy in the US (CDC, 2002) and throughout the world (eg, Croxford & Viljoen, 1999; Riley et al, 2003; Jacobson et al, 2006) As many as 13% of infants born in the US are exposed to varying levels of alcohol during pregnancy, with a higher percentage found among disadvantaged populations (CDC, 2002) Identification of alcohol affected children continues to be difficult due to the lack of specificity in behavioral diagnostic criteria and limited understanding of the pathophysiology of the disorder We have recently identified impaired eyeblink conditioning (EBC) to be a remarkably consistent deficit associated with fetal alcohol exposure (Jacobson et al, 2008) In the 5-year follow-up assessment of a cohort of heavily alcohol-exposed children recruited prenatally, not a single child with full FAS met criterion for conditioning, as contrasted with 750% of controls A large proportion (638%) of the heavily alcohol-exposed nondysmorphic children also failed to meet criterion for conditioning at this age These findings corroborate a report of poorer EBC in a US sample of school-aged, alcohol-exposed children with dyslexia (Coffin et al, 2005) Our study was conducted in Cape Town, South Africa, where there is a very high prevalence of heavy alcohol use during pregnancy in the Cape Coloured (mixed ancestry) community (Croxford & Viljoen, 1999; Jacobson et al, 2008) The estimated incidence of FAS in this population is 18 to 141 times greater than in the US and among the highest in the world (May et al, 2000) This population, composed mainly of descendants of white European settlers, Malaysian slaves, Khoi-San aboriginals, and black African ancestors, has historically comprised the large majority of workers in the wine-producing and fruit-growing region of the Western Cape The high prevalence of FAS is a consequence of the very heavy maternal drinking during pregnancy commonly found in this community, due to poor psychosocial circumstances and the traditional dop system, in which farm laborers were paid, in part, with wine Although the dop system has been outlawed, heavy alcohol consumption persists in certain sectors in urban and rural Cape Coloured communities (Carter et al, 2005; Jacobson et al, 2006), and weekend binge drinking is a major source of recreation for many in the community The EBC deficits we reported in alcohol-exposed children are consistent with animal studies showing that heavy exposure to alcohol during the equivalent of the third trimester of pregnancy in humans disrupts EBC in weanling and adult rats, a deficit that is mediated by a dose-dependent cell loss and altered neural activity in the deep cerebellar nuclei (Green et al, 2002a,b) Binge exposure during this period in rodents is also associated with loss of Purkinje and granule cells in the cerebellum (Dunty et al, 2001; Hamre & West, 1993), even after only 2 days of exposure (Thomas et al, 1998) Heavy alcohol exposure in rats and mice on even a single occasion during synaptogenesis has been found to trigger acute neurodegeneration via enhanced apoptosis of Purkinje cells and other neurons in key components of the neural circuit that mediates EBC, including the deep cerebellar nuclei, cerebellar cortex, pontine nuclei, and inferior olive (Dikranian et al, 2005; Green, 2004) The earliest autopsy studies in humans reporting damaging effects of heavy prenatal alcohol exposure identified errors in cell migration, agenesis or thinning of the corpus callosum, and anomalies in the cerebellum and brain stem (Jones & Smith, 1973; Clarren, 1977; Clarren & Smith, 1978) In the only study to perform a comprehensive morphometric analysis of the four major cortical lobes, cerebellum, and principal subcortical regions, Archibald et al (2001) found a significant deficit in total brain volume, with proportionately greater reductions particularly in the cerebellum, parietal lobe, and caudate nucleus, including a 15% reduction in cerebellar volume in individuals with FAS By contrast, hippocampal volume was not affected Pavlovian conditioning is a culturally neutral, non-verbal form of associative learning, in which the onset of a conditioned stimulus (CS), usually a pure tone, precedes an unconditioned stimulus (US), usually a mild air puff to the eye, which elicits a reflexive eyeblink unconditioned response (UR) With repeated pairings of the tone and air puff, the tone CS comes to elicit an eyeblink response on a large percentage of trials This eyeblink conditioned response (CR) represents the learned association between tone and air puff The operational simplicity and minimal sensory, motor, and motivational demands of the procedure make it applicable with little or no modification across a range of animal species—rodents, rabbits, monkeys, sheep, humans—and across the life-span, beginning in early infancy (Stanton, Claflin & Herbert, 2010) In delay conditioning, the tone CS precedes, overlaps, and co-terminates with the onset of the air puff, whereas in trace conditioning, there is a brief stimulus-free “trace interval” between the offset of the tone and the onset of the air puff (Fig 1) Figure 1 Schematic diagram of trial epochs used in short delay and trace conditioning The neural circuitry involved in eyeblink conditioning has been documented in considerable detail (Woodruff-Pak & Steinmetz, 2000a, b; Woodruff-Pak & Disterhoft, 2008) A brain stem-cerebellar circuit has been identified that is both necessary and sufficient for delay conditioning (McCormick & Thompson, 1984; Thompson, 1986; Lavond et al, 1993; Logan & Grafton, 1995; Kim & Thompson, 1997; Thompson, 2005) In delay conditioning, neural activity representing the tone CS is projected via the colliculus to discrete portions of the pontine nuclei, which convey this information to the cerebellum via mossy fibers in the middle cerebellar peduncle Neural activity representing the air-puff US is projected via the inferior olive to the cerebellum via climbing fiber projections in the inferior peduncle Both pontine and olivary inputs reach Purkinje cells in cerebellar cortex and send collateral inputs directly to the cerebellar deep nuclei (Christian & Thompson, 2003; Lavond & Steinmetz 1989) Neural plasticity in cerebellar cortex and deep nuclei produced by appropriately timed activation of climbing- and mossy-fiber inputs underlies short-delay conditioning (Thompson, 1986, 2005; Krupa et al, 1993; Kim & Thompson, 1997; Ohyama et al, 2003) The essential efferent CR pathway consists of fibers that project from the deep nuclei via the superior cerebellar peduncle to the red nucleus The CR-related neural activity is then projected to the motor neurons that generate conditioned eyeblinks Although this brain stem-cerebellar circuitry is sufficient for delay conditioning, trace conditioning with a 500-ms stimulus-free interval has been shown to engage both the cerebellum and the hippocampus in experiments with laboratory animals (Moyer et al 1990; Stanton et al, 2010; Steinmetz, 2000; Woodruff-Pak & Disterhoft, 2008) Findings from human studies suggest that a trace interval of 500 ms impairs conditioning in medial temporal lobe amnesiacs (McGlinchey-Berroth et al, 1997) and activates the hippocampus more than delay conditioning in normal adults (Cheng et al, 2008) However, temporal lobe damage does not always impair conditioning with a 500 ms trace interval (Woodruff-Pak, 1993); whereas this damage appears to entirely prevent conditioning involving a 1000 ms trace interval (eg, Clark & Squire, 1998) Eyeblink conditioning emerges gradually over the course of development in both rodents (Stanton & Freeman, 2000) and humans (Ivkovich et al, 2000; Stanton et al, 2010) By 5 months post-term, normal human infants reach the same terminal level of conditioning as adults in the short delay procedure (Herbert et al, 2003) The aims of this study were (1) to replicate our previous findings of a fetal alcohol-related deficit on delay EBC seen in children at 5 years in a new sample of school-age, heavily alcohol exposed children; (2) to determine whether increased maturation between 5 and 9 years of age attenuates the alcohol effect of prenatal alcohol exposure on delay EBC; (3) to determine if trace conditioning is also impaired in children with fetal alcohol exposure and, if so, whether this task is more or less sensitive to this exposure than delay conditioning; (4) to examine whether retention of the delay CR after a 15-year period is altered by fetal alcohol exposure and whether alcohol exposure affects the rate of extinction of this response; (5) to determine if the effects of prenatal alcohol exposure on delay and trace conditioning are independent of the effects of this exposure on IQ; (6) to examine effects of prenatal alcohol exposure on precision of timing of the eyeblink CR; and (7) to determine whether extended training can result in conditioning in exposed children who do not initially meet learning criterion

Neural correlates of Pavlovian‐to‐instrumental transfer in the nucleus accumbens shell are selectively potentiated following cocaine self‐administration

Abstract: During Pavlovian-to-instrumental transfer (PIT), learned Pavlovian cues significantly modulate ongoing instrumental actions. This phenomenon is suggested as a mechanism under which conditioned stimuli may lead to relapse in addicted populations. Following discriminative Pavlovian learning and instrumental conditioning with sucrose, one group of rats (naive) underwent electrophysiological recordings in the nucleus accumbens core and shell during a single PIT session. Other groups, following Pavlovian and instrumental conditioning, were subsequently trained to self-administer cocaine with nosepoke responses, or received yoked saline infusions and nosepoked for water rewards, and then performed PIT while electrophysiological recordings were taken in the nucleus accumbens. Behaviorally, although both naive and saline-treated groups showed increases in lever pressing during the conditioned stimulus cue, this effect was significantly enhanced in the cocaine-treated group. Neurons in the core and shell tracked these behavioral changes. In control animals, core neurons were significantly more likely to encode general information about cues, rewards and responses than those in the shell, and positively correlated with behavioral PIT performance, whereas PIT-specific encoding in the shell, but not core, tracked PIT performance. In contrast, following cocaine exposure, there was a significant increase in neural encoding of all task-relevant events that was selective to the shell. Given that cocaine exposure enhanced both behavior and shell-specific task encoding, these findings suggest that, whereas the core is important for acquiring the information about cues and response contingencies, the shell is important for using this information to guide and modulate behavior and is specifically affected following a history of cocaine self-administration.

Gamma-Band Activation Predicts Both Associative Memory and Cortical Plasticity

Abstract: Gamma-band oscillations are a ubiquitous phenomenon in the nervous system and have been implicated in multiple aspects of cognition. In particular, the strength of gamma oscillations at the time a stimulus is encoded predicts its subsequent retrieval, suggesting that gamma may reflect enhanced mnemonic processing. Likewise, activity in the gamma-band can modulate plasticity in vitro. However, it is unclear whether experience-dependent plasticity in vivo is also related to gamma-band activation. The aim of the present study was to determine whether gamma activation in primary auditory cortex modulates both the associative memory for an auditory stimulus during classical conditioning and its accompanying specific receptive field plasticity. Rats received multiple daily sessions of single tone/shock trace and two-tone discrimination conditioning, during which local field potentials and multiunit discharges were recorded from chronically implanted electrodes. We found that the strength of tone-induced gamma predicted the acquisition of associative memory 24 h later and ceased to predict subsequent performance once asymptote was reached. Gamma activation also predicted receptive field plasticity that specifically enhanced representation of the signal tone. This concordance provides a long-sought link between gamma oscillations, cortical plasticity, and the formation of new memories.

The RUB Cage: Respiration–Ultrasonic Vocalizations–Behavior Acquisition Setup for Assessing Emotional Memory in Rats

Abstract: In animals, emotional memory is classically assessed through pavlovian fear conditioning in which a neutral novel stimulus (conditioned stimulus) is paired with an aversive unconditioned stimulus. After conditioning, the conditioned stimulus elicits a fear response characterized by a wide range of behavioral and physiological responses. Despite the existence of this large repertoire of responses, freezing behavior is often the sole parameter used for quantifying fear response, thus limiting emotional memory appraisal to this unique index. Interestingly, respiratory changes and ultrasonic vocalizations (USV) can occur during fear response, yet very few studies investigated the link between these different parameters and freezing. The aim of the present study was to design an experimental setup allowing the simultaneous recording of respiration, USV, and behavior (RUB cage), and the offline synchronization of the collected data for fine-grain second by second analysis. The setup consisted of a customized plethysmograph for respiration monitoring, equipped with a microphone capturing USV, and with four video cameras for behavior recording. In addition, the bottom of the plethysmograph was equipped with a shock-floor allowing foot-shock delivery, and the top received tubing for odor presentations. Using this experimental setup we first described the characteristics of respiration and USV in different behaviors and emotional states. Then we monitored these parameters during contextual fear conditioning and showed that they bring complementary information about the animal's anxiety state and the strength of aversive memory. The present setup may be valuable in providing a clearer appraisal of the physiological and behavioral changes that occur during acquisition as well as retrieval of emotional memory.

mGluR5 positive allosteric modulation enhances extinction learning following cocaine self-administration.

Abstract: One of the most problematic issues in the treatment of drug-addiction is the persistence of drug craving and drug-seeking behavior long after the symptoms of acute drug withdrawal have subsided. As a result of chronic and repetitive drug use, drug-associated cues and contexts acquire an excessive degree of motivational salience. This “hypersalience” of drug-associated cues and contexts is a result of associative overlearning produced by the drug’s ability to create strong and lasting associations between its euphorigenic effects and the cues and contexts that are present when the drug is administered. As a result, these cues and contexts can often trigger memories of prior drug use and drug craving (an intense desire for the drug that is often evoked by drug-associated contexts and cues), which may result in drug-seeking behavior and ultimately relapse. In addition to associative overlearning, the ritualistic nature of chronic drug-taking behavior transitions from self-regulated to compulsive and habitual, representing a form of maladaptive instrumental overlearning. The two forms of overlearning result in behavioral inflexibility and perseverance of drug-seeking that is resistant to change during the course of treatment, and are often a cause for relapse and noncompliance with different treatment regimens (Childress et al., 1999; Cleva & Gass, 2010; Kalivas, Volkow, & Seamans, 2005). Extinction is defined as the gradual reduction of a conditioned response (CR) when the CR is no longer reinforced or the unconditioned stimulus (US) is no longer presented in the presence of conditioned stimulus (CS). Repeated pairings of a discrete CS (i.e., a light and/or tone) with a US (i.e., drug infusion) enables the CS to evoke specific behaviors since the CS is associated with and predicts the availability of the US. Extinction can be defined as a decline in the magnitude and/or frequency of the CR either within a single extinction training session as well as over successive extinction training sessions conducted on a routine basis (i.e., daily or weekly). Extinction is a process of new and active learning (Bouton, 2000, 2004), and as with other forms of learning and memory, it consists of separate phases including acquisition, consolidation, recall, and reconsolidation (Lee, 2009; Myers & Carlezon, 2010b; Taylor, Olausson, Quinn, & Torregrossa, 2009). In behavioral terms, acquisition of extinction learning occurs when the organism first begins to learn that the CS no longer results in the presentation of the US. Enhancement of the acquisition of extinction learning can be achieved via experimental manipulations performed prior to extinction training sessions. Consolidation, on the other hand, is the strengthening and storage of new CS-US expectancies and relationships that carry forward from one extinction training session to the next. Enhancement of the consolidation of extinction learning can be achieved via experimental manipulations performed following extinction training sessions. Finally, reconsolidation is a process by which prior extinction memories are recalled and then reconsolidated back into long-term memory. However, recent evidence suggests that memories that are recalled and reconsolidated are labile and amenable to modification (Lee, 2009; Taylor, Olausson, Quinn, & Torregrossa, 2009). Cellular hallmarks of learning and memory and associated synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD) of synaptic efficacy require glutamatergic transmission in order to occur (Miyamoto, 2006; Rao & Finkbeiner, 2007; Reis et al., 2009; Riedel, Platta, & Micheaub, 2003; Robbins & Murphy, 2006), suggesting that potentiation of glutamate-mediated neural plasticity could serve as an effective adjunct for facilitating extinction learning. Recent studies have shown that potentiation of glutamatergic transmission with ligands such as the N-methyl-D-aspartate (NMDA) partial agonist D-cycloserine (DCS), the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor potentiator 2-[2,6-difluoro-4-({2-[(phenylsulfonyl)amino]ethyl}thio)phenoxy]acetamide (PEPA), or the cystine prodrug N-acetylcysteine (NAC, which stimulates the cystine-glutamate exchanger and normalizes drug-induced deficits in extracellular glutamate during drug withdrawal), reduce extinction responding following active drug self-administration, reduce re-acquisition of drug intake, or facilitate the extinction of a conditioned place preference (CPP) produced by drugs of abuse (Botreau, Paolone, & Stewart, 2006; LaLumiere, Niehoff, & Kalivas, 2010; Nic Dhonnchadha et al., 2010; Thanos, Bermeo, Wang, & Volkow, 2009; Torregrossa, Sanchez, & Taylor, 2010; Zhou & Kalivas, 2008). DCS has also been shown to facilitate the extinction of a naloxone-induced conditioned place aversion in morphine-dependent rats (Myers & Carlezon, 2010a), suggesting that this compound may facilitate the extinction of both appetitive and aversive drug-associated memories. Collectively, these findings suggest that extinction learning can be augmented through pharmacological manipulation of glutamate transmission (Cleva, Gass, Widholm, & Olive, in press; Myers & Carlezon, 2010b; Myers, Carlezon, & Davis, in press). An alternative strategy to enhancing glutamatergic transmission, and therefore possibly extinction learning, is by allosteric potentiation of the function of type 5 metabotropic glutamate receptors (mGluR5). These receptors are predominantly localized to the perisynaptic annulus of postsynaptic dendritic spines, where they are positively coupled to NMDA receptor function and mediate various forms of synaptic plasticity (Ayala et al., 2009; Gladding, Fitzjohn, & Molnar, 2009; Luscher & Huber, 2010) and learning and memory (Simonyi, Schachtman, & Christoffersen, 2010). For example, potentiation of mGluR5 function has been shown to enhance the induction of LTP and LTD in CA1 region of the hippocampus and improve performance in a spatial memory task (Ayala et al., 2009; Popkirov & Manahan-Vaughan, in press; Rosenbrock et al., 2010). Potentiation of mGluR5 function has also been shown to facilitate the extinction of a cocaine conditioned place preference (Gass & Olive, 2009), an effect that is reversed by blockade of either mGluR5 or NMDA receptors. In contrast, mice carrying a null mutation in the gene encoding the mGluR5 receptor protein show deficits in extinction learning following cue or contextual fear conditioning (Xu, Zhu, Contractor, & Heinemann, 2009). These data strongly support a role for mGluR5 receptors in extinction learning. In the present study, we sought to determine if enhancement of mGluR5 receptor function by the mGluR5 positive allosteric modulator (PAM) 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) would enhance extinction learning following intravenous cocaine self-administration, as evidenced by reductions in the number of presses on a lever that previously resulted in intravenous cocaine delivery. We also sought to determine if CDPPB-treated animals would require fewer extinction training sessions to reach pre-defined extinction criteria as compared with vehicle-treated animals. A tertiary aim of the present study was to determine if CDPPB would enhance both the acquisition and consolidation of extinction learning, as assessed by administration of the compound prior to or immediately following extinction training sessions. Finally, to rule out the possibility that any observed reductions in lever pressing during extinction produced by CDPPB might be attributable to non-specific motor effects, we also tested the effects of this compound on open field locomotor activity.

Learning Stimulus Intervals—Adaptive Timing of Conditioned Purkinje Cell Responses

Abstract: Classical conditioning of motor responses, such as the eyeblink response, is an experimental model of associative learning and of adaptive timing of movements. A conditioned blink will have its maximum amplitude near the expected onset of the unconditioned blink-eliciting stimulus and it adapts to changes in the interval between the conditioned and unconditioned stimuli. Previous studies have shown that an eyeblink conditioning protocol can make cerebellar Purkinje cells learn to pause in response to the conditioned stimulus. According to the cerebellar cortical conditioning model, this conditioned Purkinje cell response drives the overt blink. If so, the model predicts that the temporal properties of the Purkinje cell response reflect the overt behaviour. To test this prediction, in vivo recordings of Purkinje cell activity were performed in decerebrate ferrets during conditioning, using direct stimulation of cerebellar mossy and climbing fibre afferents as conditioned and unconditioned stimuli. The results show that Purkinje cells not only develop a change in responsiveness to the conditioned stimulus. They also learn a particular temporal response profile where the timing, not only of onset and maximum but also of offset, is determined by the temporal interval between the conditioned and unconditioned stimuli.

Counterconditioning: an effective technique for changing conditioned preferences.

Abstract: The evidence for the effectiveness of counterconditioning as a strategy for changing conditioned preferences is rather scarce and inconclusive. The present experiment reinvestigated this issue and compared the effect of further conditioning, extinction, and a counterconditioning procedure on recently acquired conditioned preferences in a picture-taste paradigm. Self-report and affective priming data indicated that whereas further conditioning and extinction trials were ineffective in fully eliminating the previously acquired evaluations, the counterconditioning treatment did succeed in doing this. A follow-up valence assessment revealed that all these effects persisted after a 7-day delay period.

Mind the Gap: Olfactory Trace Conditioning in Honeybees

Abstract: Trace conditioning is a form of classical conditioning, where a neutral stimulus (conditioned stimulus, CS) is associated with a following appetitive or aversive stimulus (unconditioned stimulus, US). Unlike classical delay conditioning, in trace conditioning there is a stimulus-free gap between CS and US, and thus a poststimulus neural representation (trace) of the CS is required to bridge the gap until its association with the US. The properties of such stimulus traces are not well understood, nor are their underlying physiological mechanisms. Using behavioral and physiological approaches, we studied appetitive olfactory trace conditioning in honeybees. We found that single-odor presentation created a trace containing information about odor identity. This trace conveyed odor information about the initial stimulus and was robust against interference by other odors. Memory acquisition decreased with increasing CS–US gap length. The maximum learnable CS–US gap length could be extended by previous trace-conditioning experience. Furthermore, acquisition improved when an additional odor was presented during the CS–US gap. Using calcium imaging, we tested whether projection neurons in the primary olfactory brain area, the antennal lobe, contain a CS trace. We found odor-specific persistent responses after stimulus offset. These post-odor responses, however, did not encode the CS trace, and perceived odor quality could be predicted by the initial but not by the post-odor response. Our data suggest that olfactory trace conditioning is a less reflexive form of learning than classical delay conditioning, indicating that odor traces might involve higher-level cognitive processes.

What you see is what will change: evaluative conditioning effects depend on a focus on valence.

Abstract: This study investigated whether evaluative conditioning (EC) effects depend on an evaluative focus during the learning phase. An EC effect is a valence change of an originally neutral stimulus (conditioned stimulus or CS) that is due to the former pairing with a positive or negative stimulus (unconditioned stimulus or US). In three experiments, the task focus during the conditioning phase was manipulated. Participants judged CS-US pairings either with respect to their valence or with respect to another stimulus dimension. EC effects on explicit and implicit measures were found when valence was task relevant but not when the non-valent stimulus dimension was task relevant. Two accounts for the valence focus effect are proposed: (1) An additional direct learning of the relation of CS and evaluative responses in the valence focus condition, or (2) a stronger activation of US valence in the valence focus condition compared to the non-valent focus condition.

Representations of appetitive and aversive information in the primate orbitofrontal cortex

Abstract: Individuals weigh information about both rewarding and aversive stimuli to make adaptive decisions. Most studies of the orbitofrontal cortex (OFC), an area where appetitive and aversive neural subsystems might interact, have focused only on reward. Using a classical conditioning task where novel stimuli are paired with a reward or an aversive air puff, we discovered that two groups of orbitofrontal neurons respond preferentially to conditioned stimuli associated with rewarding and aversive outcomes; however, information about appetitive and aversive stimuli converges on individual neurons from both populations. Therefore, neurons in the OFC might participate in appetitive and aversive networks that track the motivational significance of stimuli even when they vary in valence and sensory modality. Further, we show that these networks, which also extend to the amygdala, exhibit different rates of change during reversal learning. Thus, although both networks represent appetitive and aversive associations, their distinct temporal dynamics might indicate different roles in learning processes.

The role of striatal tonically active neurons in reward prediction error signaling during instrumental task performance.

Abstract: The detection of differences between predictions and actual outcomes is important for associative learning and for selecting actions according to their potential future reward. There are reports that tonically active neurons (TANs) in the primate striatum may carry information about errors in the prediction of rewards. However, this property seems to be expressed in classical conditioning tasks but not during performance of an instrumental task. To address this issue, we recorded the activity of TANs in the putamen of two monkeys performing an instrumental task in which probabilistic rewarding outcomes were contingent on an action in block-design experiments. Behavioral evidence suggests that animals adjusted their performance according to the level of probability for reward on each trial block. We found that the TAN response to reward was stronger as the reward probability decreased; this effect was especially prominent on the late component of the pause-rebound pattern of typical response seen in these neurons. The responsiveness to reward omission was also increased with increasing reward probability, whereas there were no detectable effects on responses to the stimulus that triggered the movement. Overall, the modulation of TAN responses by reward probability appeared relatively weak compared with that observed previously in a probabilistic classical conditioning task using the same block design. These data indicate that instrumental conditioning was less effective at demonstrating prediction error signaling in TANs. We conclude that the sensitivity of the TAN system to reward probability depends on the specific learning situation in which animals experienced the stimulus-reward associations.

Associative olfactory learning in the desert locust, Schistocerca gregaria

Abstract: Locusts can learn associations between olfactory stimuli and food rewards, and use the acquired memories to choose between foods according to their nutrient requirements. They are a model system for both the study of olfactory coding and insect nutritional regulation. Previous studies have used operant paradigms for conditioning freely moving locusts, restricting the study of the neural mechanisms underlying the acquisition of olfactory memories, which requires restrained preparations for electrophysiological recordings. Here we present two complementary paradigms for the classical conditioning of olfactory memories in restrained desert locusts (Schistocerca gregaria). These paradigms allow precise experimental control over the parameters influencing learning. The first paradigm is based on classical (Pavlovian) appetitive conditioning. We show that opening of the maxillary palps can be used as a measure of memory acquisition. Maxillary palp opening in response to odour presentation is significantly higher in locusts trained with paired presentation of an odour and a food reward than in locusts trained either with unpaired presentation of food and odour or the odour alone. The memory formed by this conditioning paradigm lasts for at least 24 h. In the second paradigm, we show that classical conditioning of an odour memory in restrained locusts influences their decisions in a subsequent operant task. When locusts that have been trained to associate an odour with a food reward are placed in a Y-maze, they choose the arm containing that odour significantly more often than naive locusts. A single conditioning trial is sufficient to induce a significant bias for that odour for up to 4 h. Multiple- and block-trial training induce a significant bias that lasts at least 24 h. Thus, locusts are capable of forming appetitive olfactory memories in classical conditioning paradigms and can use these memories to modify their decisions.

Associative learning and conditioning theory : human and non-human applications

Abstract: Section I: Overview Things you always wanted to know about conditioning, but were afraid to ask Todd R. Schachtman and Steve Reilly Section II: Applications to Clinical Pathology Fear extinction and emotional processing theory: A critical review Seth J. Gillihan and Edna Foa Fear Conditioning and Attention to Threat: An Integrative Approach to Understanding the Etiology of Anxiety Disorders Katherine Oehlberg and Susan Mineka Behavioral techniques to reduce relapse after exposure therapy: Applications of studies of experimental extinction Mario A. Laborda, Bridget L. McConnell, and Ralph R. Miller Learning and anxiety Peter F. Lovibond Trauma, learned helplessness, its neuroscience and implication for PTSD Vincent M. LoLordo and J. Bruce Overmier Abberant attentional processes in schizophrenia as reflected in latent inhibition data Robert E. Lubow Discrimination learning process in autism: spectrum disorders: A comparator theory Phil Reed Section III: Applications to Health and Addiction Conditioned Immunomodulation Jennifer L. Szczytkowski and Donald T. Lysle Learning, Expectancy and Behavioural Control: Implications for drug use M. Vogel-Sprott and Mark T. Fillmore Applications of Contemporary Learning Theory in the Treatment of Drug Abuse Danielle E. McCarthy, Timothy B. Baker, Haruka Minami, and Vivian Yeh Internal stimuli generated by abused substances: Role of Pavlovian conditioning and its implications for drug addiction Rick A. Bevins and Jennifer E. Murray Learning to eat: The influence of food cues on what, when and how much we eat Janet Polivy, C. Peter Herman, and Laura Girz Conditional analgesia, negative feedback & error correction Moriel Zelikowsky and Michael S. Fanselow Incentives in the modification and cessation of cigarette smoking Edwin B. Fisher, Leonard Green, Amanda L. Calvert, & Russell E. Glasgow Section IV: Applications to Cognition, Social Interaction and Motivation Social learning and connectionism Frank Van Overwalle Application of associative learning paradigms to clinically relevant individual differences in cognitive processing Teresa A. Treat, John L. Kruschke, Richard J. Viken, and Richard M. McFall A review of procedural knowledge about the mental process models of evaluative conditioning Jan De Houwer Instrumental and Pavlovian Conditioning Analogues of Familiar Social Processes Robert Ervin Cramer and Robert Frank Weiss The impact of social cognition on emotional learning from and about others: A neurobiological perspective Andreas Olsson Effects of Conditioning in Advertising Todd R. Schachtman, Jennifer Walker and Stephanie Fowler Applications of Pavlovian conditioning to sexual behavior and reproduction Michael Domjan and Chana K. Akins Hot and bothered: Classical conditioning of sexual incentives in humans Heather Hoffman

Brain Mechanisms of Flavor Learning

Abstract: Once the flavor of the ingested food (conditioned stimulus, CS) is associated with a preferable (e.g., good taste or nutritive satisfaction) or aversive (e.g., malaise with displeasure) signal (unconditioned stimulus, US), animals react to its subsequent exposure by increasing or decreasing ingestion to the food. These two types of association learning (preference learning vs. aversion learning) are known as classical conditioned reactions which are basic learning and memory phenomena, leading selection of food and proper food intake. Since the perception of flavor is generated by interaction of taste and odor during food intake, taste and/or odor are mainly associated with bodily signals in the flavor learning. After briefly reviewing flavor learning in general, brain mechanisms of conditioned taste aversion is described in more detail. The CS-US association leading to long-term potentiation in the amygdala, especially in its basolateral nucleus, is the basis of establishment of conditioned taste aversion. The novelty of the CS detected by the cortical gustatory area may be supportive in CS-US association. After the association, CS input is conveyed through the amygdala to different brain regions including the hippocampus for contextual fear formation, to the supramammilary and thalamic paraventricular nuclei for stressful anxiety or memory dependent fearful or stressful emotion, to the reward system to induce aversive expression to the CS, or hedonic shift from positive to negative, and to the CS-responsive neurons in the gustatory system to enhance the responsiveness to facilitate to detect the harmful stimulus.