Unescientificwritingseminar.wikispaces.com

Prefrontal Mechanisms in Extinction
of Conditioned Fear
Gregory J. Quirk, René Garcia, and Francisco González-Lima
Interest in the medial prefrontal cortex (mPFC) as a source of behavioral inhibition has increased with the mounting evidence for afunctional role of the mPFC in extinction of conditioned fear. In fear extinction, a tone-conditioned stimulus (CS) previously pairedwith a footshock is presented repeatedly in the absence of footshock, causing fear responses to diminish. Here, we review convergingevidence from different laboratories implicating the mPFC in memory circuits for fear extinction: (1) lesions of mPFC impair recallof extinction under various conditions, (2) extinction potentiates mPFC physiological responses to the CS, (3) mPFC potentiation iscorrelated with extinction behavior, and (4) stimulation of mPFC strengthens extinction memory. These findings support Pavlov’soriginal notion that extinction is new learning, rather than erasure of conditioning. In people suffering from posttraumatic stressdisorder (PTSD), homologous areas of ventral mPFC show morphological and functional abnormalities, suggesting that extinctioncircuits are compromised in PTSD. Strategies for augmenting prefrontal function for clinical benefit are discussed. Key Words: Amygdala, infralimbic, long-term potentiation, prelim-
in rodents supporting this hypothesis. We also suggest ways in which prefrontal mechanisms of extinction may be augmentedso as to enhance extinction, with potential clinical applications.
Thestudyoffearandanxietyinexperimentalanimalshas LesionStudies
advanced rapidly with the use of Pavlovian fear condition-ing, in which a tone-conditioned stimulus (CS) is associ- The idea that extinction circuits involved the prefrontal cortex ated with a footshock unconditioned stimulus (US). Conditioned originated with early primate studies of appetitive conditioning, fear reactions to the tone extinguish in the absence of the shock.
in which lesions of the ventral mPFC (vmPFC) and orbitofrontal The resurgence of interest in extinction is due in large part to its cortex resulted in increased responding during extinction potential applicability to the treatment of anxiety disorders, such for a complete history of prefrontal cortex in extinc- as posttraumatic stress disorder (PTSD), in which extinction is thought to be compromised. A thorough understanding of the neural circuits of extinction of fear could yield new treatments for observed that rats with vmPFC lesions could acquire fear nor- augmenting exposure-based therapies that are used to treat mally but had difficulty extinguishing across several days of In his classic investigation of appetitive conditioning in dogs, that rats with vmPFC lesions that were centered on the infralim- Pavlov observed that extinguished responses spontaneously bic cortex (IL) could extinguish normally within a session but recovered with the passage of time This suggested had difficulty recalling extinction 24 hours later, suggesting that that extinction did not erase the memory for conditioning but IL is not required for fear inhibition under all circumstances but represented new learning. More recent behavioral studies have is important for recalling extinction after a long delay. Other confirmed and extended this finding for conditioned fear studies have confirmed that vmPFC lesions impair recall of extinction does not erase the conditioning memory, it must form a new memory that inhibits the conditioned response. This suggests that some structure or structures are activated byextinction, so as to excite inhibitory circuits that are responsible Recording Studies
for reducing the expression of fear Despite early Lesion studies presuppose that regional contributions to brain theoretical formulations of extinction-related inhibition function may be inferred from a damaged brain. A more direct the search for inhibitory circuits largely approach is to record from neuronal activity in awake animals undergoing extinction training. Do mPFC neurons signal extinction? However, studies that build on recent advances in the Paralleling mPFC lesion findings, single neurons in IL did not signal acquisition of conditioned fear point to the medial prefrontal the tone CS during acquisition or extinction training cortex (mPFC) as an important part of the neural circuit for fear The next day, however, when rats were recalling extinction. In this review, we describe converging evidence from extinction, IL units showed potentiation of short-latency tone re- lesion, recording, metabolic, stimulation, and microinfusion studies sponses The larger the tone response, the lower thespontaneous recovery of freezing, consistent with IL-mediatedinhibition of fear after extinction. No such potentiation was ob- From the Department of Physiology (GJQ), Ponce School of Medicine, served in adjacent prelimbic cortex. Thus, extinction potentiated Ponce, Puerto Rico; Neurobiologie et Psychopathologie (RG), Universite auditory inputs to IL neurons, providing direct support for the de Nice-Sophia Antipolis, Nice, France; and the Institute for Neuro- Pavlov-Konorski hypothesis that extinction potentiates neuronal science and Department of Psychology (FGL), University of Texas at activity in structures that are involved in inhibition of the condi- Address reprint requests to Gregory J. Quirk, Ph.D., Department of Physiol- ogy, Ponce School of Medicine, P.O. Box 7004, Ponce, Puerto Rico 00732; What inputs to mPFC might become potentiated as a result of Received August 1, 2005; revised October 16, 2005; accepted March 3, 2006.
whether repeated presentations of a tone CS in the absence of doi:10.1016/j.biopsych.2006.03.010 2006 Society of Biological Psychiatry behavioral networks. Metabolic responses to a test tone were compared in groups of mice that received fear conditioning, a pseudorandom treatment (unpaired tones and shocks), or con- ditioning followed by extinction. Consistent with single-unit andevoked-potential recording, the largest increase in metabolic activityafter extinction occurred in the mPFC. The infralimbic (but not theprelimbic) area showed significantly more metabolic activity thancontrols. In addition to IL, significant metabolic increases were Conditioning Extinction
observed in dorsal, medial, and lateral frontal cortex, which areareas not yet studied with the unit-recording technique. Hence, Figure 1. Schematic relating conditioned behavior to memory for condi-
multiple prefrontal regions may play a role in extinction memory.
tioning and extinction. As first suggested by Pavlov, extinction training does There also were changes in the interaction between the prefron- not eliminate memory for conditioning but generates a new memory that tal cortex and other regions, particularly in auditory and limbic competes with conditioning for control of behavior. For conditioned fear,this schema suggests that there are structures in the brain that increase their networks. In support of an inhibitory role, FDG labeling in neuronal activity with extinction, so as to drive down fear via inhibition of dmPFC, in IL cortex, and in dorsal and lateral frontal cortex was correlated significantly with extinction behavior Finally, there was a strong negative correlation between the US induces long-term potentiation (LTP) in the mPFC. The prefrontal areas and regions thought to be involved in expression mPFC receives glutamatergic inputs from the hippocampus of conditioned fear, such as the ventral tegmental area, MD thalamus, and the entire auditory system (brainstem, thalamic, High-frequency stimulation of each of these input areas results in These mapping data suggest that extinction training engages a network of interactive brain regions, which may serve two functions: to inhibit the conditioned response after extinction pathways have confirmed development of LTP-like changes in and to preserve some of the original CS-US associative effects the mPFC with extinction training. MD-evoked responses inmPFC show little change during extinction training but areincreased 1–7 days after extinction Similarly, extinction-related LTP takes place in thehippocampal–mPFC pathway after extinction training Interestingly, failure to recall extinction wasassociated with inhibition of MD-evoked potentials, and depressingthe MD-mPFC pathway with low-frequency stimulation caused fullrecovery of conditioned fear after extinction Thus, extinction training results in LTP of thalamicinputs to mPFC even days after extinction, paralleling the single-unitrecording studies and indicating a role ofmPFC in long-term retention of extinction memory. Thus, inputs tothe mPFC from the thalamus, hippocampus, or the BLA maybecome potentiated after extinction.
Microinfusion data have strongly implicated the BLA in acqui- sition of extinction however, lesions of the basal nucleus have no effect on short- orlong-term memory for extinction This highlights the potentialimportance of the lateral amygdala in the acquisition of extinc-tion. Another potentially important input to mPFC is the auditoryassociation cortex in light of reports thatauditory-cortex lesions impair extinction of auditory fear condi-tioning Local inactivationof various inputs to mPFC is needed to determine which onesmay impair extinction learning and memory.
Figure 2. Converging lines of evidence showing that the infralimbic pre-
Metabolic Mapping
frontal cortex (IL) is functionally involved in recall of extinction. (A) Lesions of
IL do not prevent extinction but interfere with recall of extinction the follow-
In addition to single-unit and evoked potential recording, ing day (modified from Quirk et al 2000). (B) Unit recording shows that IL
extinction of auditory conditioning also has been investigated neurons respond to the tone only during recall of extinction, suggesting with metabolic-mapping techniques that assess the uptake of that IL tone responses are responsible for low fear after extinction (modified fluorodeoxyglucose (FDG), a radiolabeled glucose analog from Milad and Quirk, 2002). (C) Infusing the protein synthesis inhibitor
Brain activity can be mapped with FDG because anisomycin (Aniso) into the IL just before extinction (arrow) has no effect onextinction learning but blocked recall of extinction the following day (mod- brain cells use glucose and its analogs for energy metabolism ified from Santini et al 2004). These and other data suggest that extinction- An important advantage of metabolic mapping induced potentiation of prefrontal neuronal activity is necessary for sup- over electrophysiological recording methods is that the entire pression of fear after extinction. vmPFC, ventral medial prefrontal cortex; brain can be examined at once, permitting visualization of Habit., habituation; Cond., conditioning.
Table 1. Converging Lines of Evidence from Recent Rodent Studies Showing that Extinction can be Facilitated by Activation of Medial Prefrontal
Cortex (mPFC)
Electrical stimulation paired with CSa,e Field potentials evoked by thalamic stimulationb Field potentials evoked by thalamic stimulationd Long-term potentiation of thalamic inputsd Metabolic enhancement with methylene bluef from acquisition. Thus, there is remarkable convergence be- memory, although transcription inhibitors and transgenic ap- tween the three different techniques (single-unit, evoked poten- proaches will be needed to determine whether gene expression tial, metabolic mapping) in two species (rat and mouse), show- ing that extinction potentiates vmPFC responses to the tone CS These results clearly support Pavlov’s cortical inhibi- Expression of Extinction
tion hypothesis and contradict the simpler notions of extinction Once potentiated, how does mPFC inhibit fear after extinc- as unlearning or reversal of acquisition.
tion? The infralimbic subregion of mPFC has extensive projec-tions to the amygdala, as well as the amygdala’s targets in the Molecular Studies
Formation of long-term memory has been linked to a molec- If these projections are inhibitory, the IL could ular cascade involving N-methyl-D-aspartate (NMDA)-mediated override amygdala-generated fear responses. The physiological calcium entry, activation of protein kinases, gene expression, effect of many of these projections is not known, but anatomical and protein synthesis Involvement of this cascade support exists for IL-mediated inhibition of the amygdala. IL in extinction would provide support for the idea that extinction projects robustly to the region between the central and basolat- constitutes new learning. It has been known for some time that eral nuclei, containing intercalated (ITC) cells formation of long-term memory for extinction. Protein kinases responsible for feed-forward inhibition of central nucleus output and protein synthesis in the amygdala also have been implicated neurons In support of this model, electrical stimulation of the IL area decreased the excitability of brainstem- Recent evidence suggests that a similar molecular cascade oper- projecting neurons of the amygdala central nucleus ates in the mPFC during extinction. Antagonists of NMDA receptors and decreased the expression of conditioned fear According to this model extinction-induced potentiation of tone responses in IL neurons would cause prevent the formation of long-term (but not short-term) extinction feed-forward inhibition of the central nucleus, thereby prevent- when microinfused into the mPFC. In each case, delaying the ing fear signals in BLA from exiting the amygdala. Consistent infusion 2 or 4 hours after extinction eliminated the effect, consistent with this, it recently was shown that chemical stimulation of IL with a time-limited role of molecular processes in consolidation ofextinction. Western blot analysis of prefrontal tissue shows that A. Before Extinction
B. After Extinction
infusion of MAPk inhibitor PD098059 into the mPFC immediatelyafter extinction decreased levels of phosphorylated ERK2 without affecting total ERKs Future experiments will determine whether inhibition of extracellular signal-regulated ki- nase-2 (ERK2) phosphorylation is related to LTP in the MD-mPFC or hippocampal–mPFC pathways or to other inputs to the mPFC (for Does activation of the ERK-MAPk system in the mPFC trigger gene expression necessary for extinction memory? Although little Figure 3. Schema for mPFC inhibition of fear via the amygdala. (A) Before
is known about extinction-induced gene expression, it recently extinction, the tone CS activates the basolateral amygdala (BLA), which was shown that extinction training stimulates the immediate activates the central nucleus (Ce) output neurons, triggering fear responses.
(B) After extinction, prefrontal (PFC) responses to the tone are potentiated,
Controls indicated that this up-regulation was not a result which activates GABAergic intercalated cells (ITC) within the amygdala. ITCinhibition of the Ce competes with BLA excitation of Ce, effectively cancel- of tone stimulation or acquisition of fear conditioning. c-Fos is a ing fear responses. Potentiation of PFC responses to the CS and inhibition of marker of cellular activity but also can act as a transcription factor conditioned fear responses also may involve reciprocal PFC interactions with hippocampal, thalamic, and neocortical pathways. Modified with per- are consistent with a role of gene expression in extinction increased c-Fos expression in amygdala ITC cells the spontaneous recovery of conditioned freezing that normally ITC cells also exhibit NMDA-mediated plasticity is observed with the passage of time.
suggesting that they may participate in long-term An additional approach to enhancing mPFC function is the use of metabolic enhancers such as methylene blue (MB), whichimprove activity-dependent brain energy production by targeting Conflicting Lesion Evidence on the Role of the mPFC
in Extinction
memory-improving action of MB in rats first was demonstratedfor inhibitory avoidance learning Although there is much physiological evidence in favor of a functional role of mPFC in learning and expression of extinction, administration of MB could enhance retention of an extinguished there also are conflicting lesion reports. Two groups did not find conditioned response. Postextinction freezing was 50% lower in any effect of pretraining mPFC lesions on extinction of condi- rats that were receiving 4 mg/kg of MB, a dose that chronically is used in human beings without negative side effects another study found that lesions made after conditioning did not Control rats injected with MB showed no changes in motor impair subsequent extinction Interpretation activity or general fearfulness, suggesting that postextinction MB of permanent lesion effects often is hampered by potential administration specifically enhanced memory for extinction. Rats recovery of function or compensation by other structures. There with improved retention of extinction also showed a greater is a pressing need, therefore, for studies that use temporary relative increase in cytochrome oxidase activity in the same inactivation of mPFC via microinfusion of local anesthetics or the prefrontal cortical regions that are activated during extinction GABA antagonist muscimol. Preliminary reports using these techniques are conflicting, showing increased fear augmenting extinction-induced potentiation of mPFC. Note the parallel with electrical stimulation and unit-recording findings Conversely, decreases in cytochrome oxidase activity challenge for future studies will be to identify the factors that in the prefrontal cortex produced by genetic selection of rats that could account for variability between laboratories. These might are predisposed to helplessness results in include contextual variables (e.g., AAA vs. ABB designs), the rats with deficits in fear extinction that simulate the PTSD presence of a competing appetitive instrumental response (such as bar-pressing for food), or the number of extinction trials (e.g.,overtraining-induced masking of effects). Another possible rea-son for negative lesion effects is that the mPFC likely is part of a Relevance to Treatment of Psychiatric Disorders
network of structures that collectively consolidate and expressextinction memory Disconnection of a There is great interest in finding more effective treatments for sufficient number of structures within the network may be a anxiety disorders, which are among the most common mental prerequisite for observing lesion deficits. Finally, recent studies health problems. Extinction deficits have been implicated as a show that mPFC neurons can signal acquisition of fear condi- possible risk factor for the development of PTSD show reduced extinction of aversively conditioned responses separate modules within mPFC for exciting versus inhibiting fear.
and show impairments in afunctional network involving the amygdala and anterior cingu- Enhancing Prefrontal Function Strengthens Extinction
late Brain-imaging studies ofPTSD patients show reduced activity If prefrontal activation is essential for extinction learning, then stimulating prefrontal cortex should strengthen extinction. Support prefrontal cortex, an area that is homologous with extinction- for this idea comes from experiments using electrical stimulation related regions of rodent mPFC These studies and metabolic enhancers. Electrical stimulation was used to mimic also show increased amygdala activity in PTSD patients who are short-latency tone-evoked responses of infralimbic neurons (100 – suggesting a lack of top-down control of the amygdala by Pairing this brief IL stimulation with conditioned tones reduced the structures involved in extinction of fear.
expression of freezing, consistent with feed-forward inhibition of Several recent functional imaging and volumetric studies dem- amygdala output neurons mPFC stimulation also onstrate that extinction activates perigenual and associated regions strengthened extinction learning as evidenced by persistent de- creased fear responses the day after the stimulation, suggesting LTP of extinction-related synapses in mPFC.
coworkers demonstrated that retention of fear extinction was cor- The role of LTP was tested directly by enhancing mPFC related with the thickness of the vmPFC suggest- responsiveness to MD thalamic inputs by applying high-fre- ing that the likelihood of developing PTSD depends on the integrity quency stimulation before extinction training of the prefrontal extinction system. For a complete review of the MD stimulation had no effect on the rate of extinction learning within the training session, supporting lesion and Behavioral therapy for PTSD (exposure therapy) is based unit-recording findings that mPFC is not responsible for short- term extinction memory. One week later, however, retention of Therefore, methods of facilitating extinction and preventing the extinction was markedly improved in potentiated rats, as evi- return of fear may lead to more effective therapeutic interven- denced by low rates of spontaneous recovery of freezing.
tions. Current behavioral techniques such as flooding and implo- Improvement in extinction retention was correlated with poten- sion could be improved by pharmacological interventions that tiation of mPFC evoked potentials. Thus, mPFC LTP prevented accelerate and strengthen extinction. For example, a reduction in the number of exposure sessions required to successfully extin- Berretta S, Pantazopoulos H, Caldera M, Pantazopoulos P, Paré D (2005): guish fear responses could counteract the relatively high dropout Infralimbic cortex activation increases c-Fos expression in intercalated rate that is observed with this type of therapy neurons of the amygdala. Neuroscience 132:943–953.
Bouton ME (2002): Context, ambiguity, and unlearning: Sources of relapse after behavioral extinction. Biol Psychiatry 52:976 –986.
Several recent studies have shown that extinction learning in Bremner JD (2002): Neuroimaging studies in post-traumatic stress disorder.
rats can be accelerated and strengthened with systemically Curr Psychiatry Rep 4:254 –263.
applied drugs. These include the noradrenergic antagonist yo- Bremner JD (2003): Functional neuroanatomical correlates of traumatic himbine the dopamine D2 receptor antagonist stress revisited 7 years later, this time with data. Psychopharmacol Bull Burgos-Robles A, Santini E, Quirk GJ (2004): Blockade of NMDA receptors in the medial prefrontal cortex impairs consolidation of fear extinction. Soc Neurosci Abstr Program No. 328.14.
With the exception of DCS, the locus of action Butter CM, Mishkin M, Rosvold HE (1963): Conditioning and extinction of a in the brain of these drugs is not yet known. On the basis of food-rewarded response after selective ablation of frontal cortex in rhe- previous work, however, modulation of dopaminergic and nor- sus monkeys. Exp Neurol 7:65–75.
adrenergic systems in the rat mPFC is likely to modulate the rate Cain CK, Blouin AM, Barad M (2004): Adrenergic transmission facilitates extinction of conditional fear in mice. Learn Mem 11:179 –187.
DCS has been shown to be effective when infused into the Callaway NL, Riha PD, Wrubel KM, McCollum D, Gonzalez-Lima F (2002): BLA and clinical studies show that adminis- Methylene blue restores spatial memory retention impaired by an inhib-itor of cytochrome oxidase in rats. Neurosci Lett 332:83– 86.
tering DCS to acrophobic subjects who are undergoing exposure Cassell MD, Wright DJ (1986): Topography of projections from the medial therapy improves the effectiveness of the therapy prefrontal cortex to the amygdala in the rat. Brain Res Bull 17:321–333.
However, there are some limitations to this approach, such Chan KH, Morell JR, Jarrard LE, Davidson TL (2001): Reconsideration of the as CS nonspecificity and tolerance to repeated DCS role of the hippocampus in learned inhibition. Behav Brain Res 119:111– the metabolic enhancer MB A metabolic approach Charney DS (2004): Psychobiological mechanisms of resilience and vulner- differs from the transmitter-receptor approach because it is not ability: Implications for successful adaptation to extreme stress. AmJ Psychiatry 161:195–216.
selective for a single transmitter system or brain region but targets all Charney DS, Deutch AY, Krystal JH, Southwick SM, Davis M (1993): Psycho- the synapses that require increased energy during postextinction biologic mechanisms of posttraumatic stress disorder. Arch Gen Psychi- memory consolidation, such as in the various prefrontal cortex Chhatwal JP, Davis M, Maguschak KA, Ressler KJ (2005): Enhancing cannabi- activating mPFC during exposure therapy could include repetitive noid neurotransmission augments the extinction of conditioned fear.
transcranial magnetic stimulation deep brain Neuropsychopharmacology 30:516 –524.
Cohen H, Kaplan Z, Kotler M, Kouperman I, Moisa R, Grisaru N (2004): Repet- itive transcranial magnetic stimulation of the right dorsolateral prefron- Thus, prefrontal activation achieved pharmacologically, tal cortex in posttraumatic stress disorder: A double-blind, placebo- physiologically, or psychologically could serve as a useful adjunct to controlled study. Am J Psychiatry 161:515–524.
exposure therapy by strengthening memory for the extinction Condé F, Maire-Lepoivre E, Audinat E, Crepel F (1995): Afferent connections of the medial frontal cortex of the rat. II. Cortical and subcortical affer-ents. J Comp Neurol 352:567–593.
Corcoran KA, Maren S (2003): Reversible inactivation of medial prefrontal cortex disrupts the retrieval of fear extinction. Soc Neurosci Abstr 199.8.
This work was supported by NIH grants: R01-MH58883, Cox J, Westbrook RF (1994): The NMDA receptor antagonist MK-801 blocks S06-GM08239, and R21-MH072156 (to GJQ), the Philippe Foun- acquisition and extinction of conditioned hypoalgesic responses in the dation (to RG), and NIH grant R01-NS37755 (to FGL). rat. Q J Exp Psychol B 47:187–210.
Aspects of this work were presented at the conference “Extinc- Falls WA, Miserendino MJ, Davis M (1992): Extinction of fear-potentiated tion: The Neural Mechanisms of Behavior Change”, February startle: Blockade by infusion of an NMDA antagonist into the amygdala.
2– 6, 2005 in Ponce, Puerto Rico. The Conference was sponsored Farinelli M, Deschaux O, Hugues S, Thevenet A, Garcia R (in press): Hip- by the National Institute of Mental Health, National Institute on pocampal train stimulation modulates recall of fear extinction indepen- Drug Abuse, Ponce School of Medicine, University of Puerto Rico dently of prefrontal cortex synaptic plasticity and lesions. Learn Mem.
Centers of Biomedical Research Excellence (COBRE) Program, Floyd NS, Price JL, Ferry AT, Keay KA, Bandler R (2001): Orbitomedial prefron- Pfizer Global Pharmaceutical, and the Municipality of Ponce. tal cortical projections to hypothalamus in the rat. J Comp Neurol 432:307–328.
Abelson JL, Curtis GC, Sagher O, Albucher RC, Harrigan M, Taylor SF, et al Garcia R (2002): Stress, synaptic plasticity, and psychopathology. Rev Neuro- (2005): Deep brain stimulation for refractory obsessive-compulsive dis- order. Biol Psychiatry 57:510 –516.
Gewirtz JC, Falls WA, Davis M (1997): Normal conditioned inhibition and Anderson P, Jacobs C, Rothbaum BO (2004): Computer-supported cognitive extinction of freezing and fear-potentiated startle following electrolytic behavioral treatment of anxiety disorders. J Clin Psychol 60:253–267.
lesions of medical prefrontal cortex in rats. Behav Neurosci 111:712–726.
Anglada-Figueroa D, Quirk GJ (2005): Lesions of the basal amygdala block Gilboa A, Shalev AY, Laor L, Lester H, Louzoun Y, Chisin R, et al (2004): expression of conditioned fear, but not extinction. J Neurosci 25:9680 – Functional connectivity of the prefrontal cortex and the amygdala in posttraumatic stress disorder. Biol Psychiatry 55:263–272.
Baeg EH, Kim YB, Jang J, Kim HT, Mook-Jung I, Jung MW (2001): Fast spiking Gonzalez-Lima F, Bruchey AK (2004): Extinction memory improvement by and regular spiking neural correlates of fear conditioning in the medial the metabolic enhancer methylene blue. Learn Mem 11:633– 640.
prefrontal cortex of the rat. Cereb Cortex 11:441– 451.
Gottfried JA, Dolan RJ (2004): Human orbitofrontal cortex mediates extinc- Baker JD, Azorlosa JL (1996): The NMDA antagonist MK-801 blocks the tion learning while accessing conditioned representations of value. Nat extinction of Pavlovian fear conditioning. Behav Neurosci 110:618 – 620.
Barrett D, Shumake J, Jones D, Gonzalez-Lima F (2003): Metabolic mapping Hermans D, Dirikx T, Vansteenwegenin D, Baeyens F, Van den Bergh O, Eelen of mouse brain activity after extinction of a conditioned emotional re- P (2005): Reinstatement of fear responses in human aversive condition- sponse. J Neurosci 23:5740 –5749.
ing. Behav Res Ther 43:533–551.
Herry C, Garcia R (2002): Prefrontal cortex long-term potentiation, but not McDonald AJ, Mascagni F, Guo L (1996): Projections of the medial and lateral long-term depression, is associated with the maintenance of extinction prefrontal cortices to the amygdala: A Phaseolus vulgaris leucoaggluti- of learned fear in mice. J Neurosci 22:577–583.
nin study in the rat. Neuroscience 71:55–75.
Herry C, Garcia R (2003): Behavioral and paired-pulse facilitation analyses of Mickley GA, Kenmuir CL, Yocom AM, Wellman JA, Biada JM (2005): A role for long-lasting depression at excitatory synapses in the medial prefrontal prefrontal cortex in the extinction of a conditioned taste aversion. Brain cortex in mice. Behav Brain Res 146:89 –96.
Herry C, Vouimba RM, Garcia R (1999): Plasticity in the mediodorsal thalamo- Milad MR, Quinn BT, Pitman RK, Orr SP, Fischl B, Rauch SL (2005): Thickness of prefrontal cortical transmission in behaving mice. J Neurophysiol 82: ventromedial prefrontal cortex in humans is correlated with extinction memory. Proc Natl Acad Sci U S A 102:10706 –10711.
Hugues S, Chessel A, Léna I, Marsault R, Garcia R (in press): Prefrontal infusion Milad MR, Quirk GJ (2002): Neurons in medial prefrontal cortex signal mem- of PD098059 immediately after fear extinction training blocks extinc- ory for fear extinction. Nature 420:70 –74.
tion-associated prefrontal synaptic plasticity and decreases prefrontal Milad MR, Rauch SL, Pitman RK, Quirk GJ (in press): Fear extinction in rats: ERK2 phosphorylation. Synapse.
Implications for human brain imaging and anxiety disorders. Biol Hugues S, Deschaux O, Garcia R (2004): Postextinction infusion of a mitogen- activated protein kinase inhibitor into the medial prefrontal cortex im- Milad MR, Vidal-Gonzalez I, Quirk GJ (2004): Electrical stimulation of medial pairs memory of the extinction of conditioned fear. Learn Mem 11:540 – prefrontal cortex reduces conditioned fear in a temporally specific man- ner. Behav Neurosci 118:389 –394.
Hurley KM, Herbert H, Moga MM, Saper CB (1991): Efferent projections of the Morgan MA, LeDoux JE (1995): Differential contribution of dorsal and ventral infralimbic cortex of the rat. J Comp Neurol 308:249 –276.
medial prefrontal cortex to the acquisition and extinction of conditioned Jay TM, Burette F, Laroche S (1995): NMDA receptor-dependent long-term fear in rats. Behav Neurosci 109:681– 688.
potentiation in the hippocampal afferent fibre system to the prefrontal Morgan MA, Romanski LM, LeDoux JE (1993): Extinction of emotional learn- cortex in the rat. Eur J Neurosci 7:247–250.
ing: Contribution of medial prefrontal cortex. Neurosci Lett 163:109 –113.
Jay TM, Witter MP (1991): Distribution of hippocampal CA1 and subicular Morgan MA, Schulkin J, LeDoux JE (2003): Ventral medial prefrontal cortex efferents in the prefrontal cortex of the rat studied by means of antero- and emotional perseveration: The memory for prior extinction training.
grade transport of Phaseolus vulgaris-leucoagglutinin. J Comp Neurol Behav Brain Res 146:121–130.
Morrow BA, Elsworth JD, Rasmusson AM, Roth RH (1999): The role of meso- Kaczmarek L (2002): c-Fos in learning: Beyond the mapping of neuronal prefrontal dopamine neurons in the acquisition and expression of con- activity. In: Kaczmarek L, Robertson HA, editors. Handbook of Chemical ditioned fear in the rat. Neuroscience 92:553–564.
Neuroanatomy: Immediate Early Genes and Inducible Transcription Factors Myers KM, Davis M (2002): Behavioral and neural analysis of extinction.
in Mapping of the Central Nervous System Function and Dysfunction. Am- Myers KM, Davis M (2004): Temporary inactivation of the infralimbic region Kandel ER (2001): The molecular biology of memory storage: A dialogue of medial prefrontal cortex via localized infusion of muscimol or ba- between genes and synapses. Science 294:1030 –1038.
clofen does not impair conditioned inhibition or extinction of fear po- Kimble DP, Kimble RJ (1970): The effect of hippocampal lesions on extinction tentiated startle in rats. Soc Neurosci Abstr 328.2.
and “hypothesis” behavior in rats. Physiol Behav 5:735–738.
Naylor GJ, Martin B, Hopwood SE, Watson Y (1986): A two-year double-blind Konorski J (1967): Integrative Activity of the Brain. Chicago: University of crossover trial of the prophylactic effect of methylene blue in manic- depressive psychosis. Biol Psychiatry 21:915–920.
Laviolette SR, Lipski WJ, Grace AA (2005): A subpopulation of neurons in the Paré D, Smith Y (1993a): Distribution of GABA immunoreactivity in the medial prefrontal cortex encodes emotional learning with burst and amygdaloid complex of the cat. Neuroscience 57:1061–1076.
frequency codes through a dopamine D4 receptor-dependent basolat- Paré D, Smith Y (1993b): The intercalated cell masses project to the central eral amygdala input. J Neurosci 25:6066 – 6075.
and medial nuclei of the amygdala in cats. Neuroscience 57:1077–1090.
Lazar SW, Bush G, Gollub RL, Fricchione GL, Khalsa G, Benson H (2000): Parnas AS, Weber M, Richardson R (2005): Effects of multiple exposures to Functional brain mapping of the relaxation response and meditation.
Neuroreport 11:1581–1585.
D-cycloserine on extinction of conditioned fear in rats. Neurobiol Learn Lebron K, Milad MR, Quirk GJ (2004): Delayed recall of fear extinction in rats with lesions of ventral medial prefrontal cortex. Learn Mem 11:544 –548.
Pavlov I (1927): Conditioned Reflexes. London: Oxford University Press.
Ledgerwood L, Richardson R, Cranney J (2003): Effects of D-cycloserine on Peri T, Ben Shakhar G, Orr SP, Shalev AY (2000): Psychophysiologic assess- extinction of conditioned freezing. Behav Neurosci 117:341–349.
ment of aversive conditioning in posttraumatic stress disorder. Biol Psy- Ledgerwood L, Richardson R, Cranney J (2005): D-cycloserine facilitates extinction of learned fear: Effects on reacquisition and generalized ex- Phelps EA, Delgado MR, Nearing KI, LeDoux JE (2004): Extinction learning in tinction. Biol Psychiatry 57:841– 847.
humans: Role of the amygdala and vmPFC. Neuron 43:897–905.
Likhtik E, Pelletier JG, Paz R, Paré D (2005): Prefrontal control of the amyg- Pirot S, Jay TM, Glowinski J, Thierry AM (1994): Anatomical and electrophys- dala. J Neurosci 25:7429 –7437.
iological evidence for an excitatory amino acid pathway from the tha- Lin CH, Yeh SH, Lu HY, Gean PW (2003): The similarities and diversities of lamic mediodorsal nucleus to the prefrontal cortex in the rat. Eur J Neu- signal pathways leading to consolidation of conditioning and consoli- dation of extinction of fear memory. J Neurosci 23:8310 – 8317.
Ponnusamy R, Nissim HA, Barad M (2005): Systemic blockade of D2-like Lissek S, Powers AS, McClure EB, Phelps EA, Woldehawariat G, Grillon C, et al dopamine receptors facilitates extinction of conditioned fear in mice.
(2005): Classical fear conditioning in the anxiety disorders: A meta-anal- ysis. Behav Res Ther 43:1391–1424.
Quirk GJ (2002): Memory for extinction of conditioned fear is long-lasting Lu KT, Walker DL, Davis M (2001): Mitogen-activated protein kinase cascade and persists following spontaneous recovery. Learn Mem 9:402– 407.
in the basolateral nucleus of amygdala is involved in extinction of fear- Quirk GJ, Likhtik E, Pelletier JG, Paré D (2003): Stimulation of medial prefron- potentiated startle. J Neurosci 21:RC162.
tal cortex decreases the responsiveness of central amygdala output Maroun M, Richter-Levin G (2003): Exposure to acute stress blocks the induc- neurons. J Neurosci 23:8800 – 8807.
tion of long-term potentiation of the amygdala-prefrontal cortex path- Quirk GJ, Russo GK, Barron JL, Lebron K (2000): The role of ventromedial way in vivo. J Neurosci 23:4406 – 4409.
prefrontal cortex in the recovery of extinguished fear. J Neurosci 20: Martinez JL Jr, Jensen RA, Vasquez BJ, McGuinness T, McGaugh JL (1978): Methylene blue alters retention of inhibitory avoidance responses.
Rauch SL, Shin LM, Phelps EA (2006): Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research past, McCormick DA, Thompson RF (1982): Locus coeruleus lesions and resistance present and future. Biol Psychiatry 60:376 –382.
to extinction of a classically conditioned response: Involvement of the Rauch SL, Shin LM, Segal E, Pitman RK, Carson MA, McMullin K, et al (2003): neocortex and hippocampus. Brain Res 245:239 –249.
Selectively reduced regional cortical volumes in post-traumatic stress McDonald AJ (1991): Organization of amygdaloid projections to the pre- disorder. Neuroreport 14:913–916.
frontal cortex and associated striatum in the rat. Neuroscience 44:1–14.
Rescorla RA (2004): Spontaneous recovery. Learn Mem 11:501–509.
Rescorla RA, Heth CD (1975): Reinstatement of fear to an extinguished Sierra-Mercado D, Burgos-Robles A, Corcoran KA, Lebron K, Quirk GJ (2005): conditioned stimulus. J Exp Psychol Anim Behav Process 1:88 –96.
Inactivation of the ventromedial prefrontal cortex reduces the expres- Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, et sion of conditioned fear. Soc Neurosci Abstr 649.9.
al (2004): Cognitive enhancers as adjuncts to psychotherapy: Use of Sokoloff L (1992): Imaging techniques in studies of neural functions. In: D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gonzalez-Lima F, Finkenstadt T, Scheich H, editors. Advances in Metabolic Gen Psychiatry 61:1136 –1144.
Mapping Techniques for Brain Imaging of Behavior and Learning Functions.
Rhodes SE, Killcross S (2004): Lesions of rat infralimbic cortex enhance recov- ery and reinstatement of an appetitive Pavlovian response. Learn Mem Song E, Kim JJ (2004): Effects of auditory cortex lesions on acquisition and extinction of fear conditioning to two different auditory stimuli in rats.
Riha PD, Bruchey AK, Echevarria DJ, Gonzalez-Lima F (2005): Memory facili- tation by methylene blue: Dose-dependent effect on behavior and brain Sotres-Bayon F, Bush DE, LeDoux JE (2004): Emotional perseveration: An oxygen consumption. Eur J Pharmacol 511:151–158.
update on prefrontal-amygdala interactions in fear extinction. Learn Royer S, Martina M, Paré D (1999): An inhibitory interface gates impulse traffic between the input and output stations of the amygdala. J Neurosci Sotres-Bayon F, Cain CK, LeDoux JE (2006): Brain mechanisms of fear extinc- tion: Historical perspectives on the contribution of prefrontal cortex. Biol Royer S, Paré D (2002): Bidirectional synaptic plasticity in intercalated amyg- dala neurons and the extinction of conditioned fear responses. Neuro- Teich AH, McCabe PM, Gentile CC, Schneiderman LS, Winters RW, Liskowsky DR, et al (1989): Auditory cortex lesions prevent the extinction of Pavlov- Santini E, Ge H, Ren K, Pena DO, Quirk GJ (2004): Consolidation of fear ian differential heart rate conditioning to tonal stimuli in rabbits. Brain extinction requires protein synthesis in the medial prefrontal cortex.
van Minnen A, Hagenaars M (2002): Fear activation and habituation patterns Santini E, Muller RU, Quirk GJ (2001): Consolidation of extinction learning as early process predictors of response to prolonged exposure treat- involves transfer from NMDA-independent to NMDA-dependent mem-ory. J Neurosci 21:9009 –9017.
ment in PTSD. J Trauma Stress 15:359 –367.
Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, Lasko NB, et al (2004): Vertes RP (2004): Differential projections of the infralimbic and prelimbic Regional cerebral blood flow in the amygdala and medial prefrontal cortex in the rat. Synapse 51:32–58.
cortex during traumatic imagery in male and female Vietnam veterans Vouimba RM, Garcia R, Baudry M, Thompson RF (2000): Potentiation of condi- with PTSD. Arch Gen Psychiatry 61:168 –176.
tioned freezing following dorsomedial prefrontal cortex lesions does not Shin LM, Whalen PJ, Pitman RK, Bush G, Macklin ML, Lasko NB, et al (2001): An interfere with fear reduction in mice. Behav Neurosci 114:720 –724.
fMRI study of anterior cingulate function in posttraumatic stress disor- Walker DL, Davis M (2002): The role of amygdala glutamate receptors in fear der. Biol Psychiatry 50:932–942.
learning, fear-potentiated startle, and extinction. Pharmacol Biochem Shumake J, Barrett D, Gonzalez-Lima F (2005): Behavioral characteristics of rats predisposed to learned helplessness: Reduced reward sensitivity, Walker DL, Ressler KJ, Lu KT, Davis M (2002): Facilitation of conditioned fear extinc- increased novelty seeking, and persistent fear memories. Behav Brain Res tion by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci 22:2343–2351.
Shumake J, Poremba A, Edwards E, Gonzalez-Lima F (2000): Congenital Weible AP, McEchron MD, Disterhoft JF (2000): Cortical involvement in ac- helpless rats as a genetic model for cortex metabolism in depression.
quisition and extinction of trace eyeblink conditioning. Behav Neurosci

Source: http://unescientificwritingseminar.wikispaces.com/file/view/Prefrontal%20mechanism%20in%20extinction%20of%20conditioned%20Fear.pdf/79825651/Prefrontal%20mechanism%20in%20extinction%20of%20conditioned%20Fear.pdf

aofas.org

TOENAIL FUNGUS What is Toenail Fungus? Onychomycosis (toenail fungus) is an infection of the nail and sometimes surrounding tissue. It is extremely common with 20% of the general population and 75% of individuals over 60 years old affected. Frequently the problem causes cosmetic concerns, but many patients also experience pain, and infrequently toenail fungus can allow more serious inf

Cyclospora

CYCLOSPORA What is Cyclospora ? Cyclospora ( Cyclospora cayetanensis ) is a parasite that is composed of only one cell. It is too small to be seen with the naked eye (only 8-10 microns in diameter). It used to be called by such names as cyanobacterium-like, coccidia-like, and Cyclospora -like bodies (CLBs). The first known cases of Cyclospora infection were diagnosed in 1977 (rep

Copyright © 2010-2014 Medical Articles