Radley, J.J. et al. (2005). Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cerebral Cortex, 16, 313-320.
The medial prefrontal cortex (mPFC) plays an important role in higher cognitive processes and in the regulation of stress-induced HPA axis activity. This study investigated the effect of stress on dendritic spine density in the mPFC. Rats were restrained for 6 hours daily for 21 days with wire mesh. Following the 21 days of stress, stressed rats weighed less than controls, had a 20% decrease in overall apical dendritic length, a 16% decrease in apical dendritic spine density, and hence an estimated 33% reduction in the total number of axospinous synapses on apical dendrites of pyramidal neurons in the mPFC. These morphological changes may have a significant impact on the functional properties of this region. Clinically, mPFC dysfunction is associated with PTSD and depression. One potential neuroanatomical substrate relevant to these disorders is the mPFC-amygdala circuit. Normally, the mPFC may inhibit amygdala output through its connections on the GABAergic intercalated cells at the border of the lateral and central nuclei of the amygdala. Experimental lesions of the mPFC support this, leading to an enhancement of amygdala-dependent behaviors such as emotionality and fear conditioning. Future studies are needed to investigate the extent to which these morphological changes from chronic stress are reversible.
Showing posts with label Behavioral Neuroscience. Show all posts
Showing posts with label Behavioral Neuroscience. Show all posts
Wednesday, April 29, 2009
Comparisons of Stimulus Learning and Response Learning in a Punishment Situation
Bolles, R.C., Holtz, R., Dunn, T., & Hill, W. (1980). Comparisons of Stimulus Learning and Response Learning in a Punishment Situation. Learning and Motivation, 11, 78-96.
Early on in the study of learning, learning was believed to consist of the attachment of a response to a stimuli (an S-R association). Later, in contrast with the long-held conventional view that all learning was of the S-R form, alternative forms were proposed by Pavlov and others. Examples include stimulus learning (S-S*) and response learning (R-S*). What type of learning underlied punishment, for example? This stimulated debate. In common punishment paradigms, it became obvious that is was unclear whether the animal was learning that shock is correlated there contextually with the bar (stimulus) or whether shock is correlated with its behavior of pressing the bar (response). The purpose of this paper was to attempt to disentangle these different forms of learning experimentally. Four novel experimental paradigms were explored.
Experiment 1 contained one single bar in the chamber which could either be pressed or pulled. Animals had to alternate their behavioral response (press to pull, and back again) in order to be rewarded. Punishment was delivered on every tenth press for half the animals or every tenth pull for the other half. Results showed a rapid initial suppression (fear to environmental stimuli), but later a return to baseline for the unpunishment response and continued suppression for the punished response. This seems to be evidence for both types of learning taking place within one paradigm. Experiment 2 simply adjusted the response contingencies (up and down) to see if results would be sensitive to this type of experimental manipulation. Instead of an FR-10 punishment schedule, rats were shocked on FR-4 or FR-25. FR-4 showed dramatic differences in responding from the outset. FR-25 differences only emerged in the second day of punishment.
Experiment 3 used two bars, each of which could be either pressed or pulled. Thus, four punishment conditions were possible, punishing a left-press, a left-lift, a right-press, or a right-lift. Results showed that when a rat was punished for a left-lift, for example, it quickly stopped lifting AND pressing the left bar. However, it continued to lift AND press the right bar. Thus, learning, in this case, seems to be mostly about stimuli. Experiment 4, like Experiment 2, changed the contingencies. Punishment was shifted from an FR-1 schedule to an FR-10 schedule. Punishment conditions were: press or lift left bar, press or lift right bar, lifting left or right, and pressing left or right. Across the conditions, the general trend that emerged was a rapid emergence of stimulus learning and then a slower but undeniable development of response learning.
Early on in the study of learning, learning was believed to consist of the attachment of a response to a stimuli (an S-R association). Later, in contrast with the long-held conventional view that all learning was of the S-R form, alternative forms were proposed by Pavlov and others. Examples include stimulus learning (S-S*) and response learning (R-S*). What type of learning underlied punishment, for example? This stimulated debate. In common punishment paradigms, it became obvious that is was unclear whether the animal was learning that shock is correlated there contextually with the bar (stimulus) or whether shock is correlated with its behavior of pressing the bar (response). The purpose of this paper was to attempt to disentangle these different forms of learning experimentally. Four novel experimental paradigms were explored.
Experiment 1 contained one single bar in the chamber which could either be pressed or pulled. Animals had to alternate their behavioral response (press to pull, and back again) in order to be rewarded. Punishment was delivered on every tenth press for half the animals or every tenth pull for the other half. Results showed a rapid initial suppression (fear to environmental stimuli), but later a return to baseline for the unpunishment response and continued suppression for the punished response. This seems to be evidence for both types of learning taking place within one paradigm. Experiment 2 simply adjusted the response contingencies (up and down) to see if results would be sensitive to this type of experimental manipulation. Instead of an FR-10 punishment schedule, rats were shocked on FR-4 or FR-25. FR-4 showed dramatic differences in responding from the outset. FR-25 differences only emerged in the second day of punishment.
Experiment 3 used two bars, each of which could be either pressed or pulled. Thus, four punishment conditions were possible, punishing a left-press, a left-lift, a right-press, or a right-lift. Results showed that when a rat was punished for a left-lift, for example, it quickly stopped lifting AND pressing the left bar. However, it continued to lift AND press the right bar. Thus, learning, in this case, seems to be mostly about stimuli. Experiment 4, like Experiment 2, changed the contingencies. Punishment was shifted from an FR-1 schedule to an FR-10 schedule. Punishment conditions were: press or lift left bar, press or lift right bar, lifting left or right, and pressing left or right. Across the conditions, the general trend that emerged was a rapid emergence of stimulus learning and then a slower but undeniable development of response learning.
Wednesday, December 3, 2008
Symmetrical effects of amphetamine and alpha-flupenthixol on conditioned punishment and conditioned reinforcement: contrasts with midazolam
Killcross, A.S., Everitt, B.J., & Robbins, T.W. (1997). Symmetrical effects of amphetamine and alpha-flupenthixol on conditioned punishment and conditioned reinforcement: contrasts with midazolam. Psychopharmacology, 129, 141-152.
There is evidence to suggest that forebrain dopaminergic systems are likely to be involved in both appetitive and aversive motivation. These authors studied the effects of dopamine (DA) agents on conditioned punishment (aversive learning) and conditioned reinforcement (appetitive learning) paradigms using DA agonists and antagonists injected systemically. In conditioned punishment, a Pavlovian CS predicting punishment is added to an instrumental bar-pressing paradigm, but only on one of the bars. Normal animals will adjust their bar-pressing away from this lever. (Note: These authors, however, implemented a punishment procedure by presenting a CS and shock upon bar-press, rather than a conditioned punishment procedure which would only present the CS upon bar-press). In conditioned reinforcement, a CS predicting reward is added to the instrumental bar-pressing paradigm on one of the bars. Animals will naturally come to favor this bar paired with the appetitive CS.
DA agonists increased the effect of a punishing CS, causing the animals to further decrease their bar pressing. DA agonists also enhanced the effect of an appetitive CS, increasing bar pressing. DA antagonists, on the other hand, decreased the effect of a punishing CS. They also reduced the effect of an appetitive CS. Thus, it appears dopaminergic agents modulate the behavioral impact of both appetitively and aversively motivated conditioned stimuli on instrumental performance. Systemic benzodiazepene administration was also explored with results showing a selective impact on aversively-motivated stimuli (i.e. no effect on the appetitive CS).
There is evidence to suggest that forebrain dopaminergic systems are likely to be involved in both appetitive and aversive motivation. These authors studied the effects of dopamine (DA) agents on conditioned punishment (aversive learning) and conditioned reinforcement (appetitive learning) paradigms using DA agonists and antagonists injected systemically. In conditioned punishment, a Pavlovian CS predicting punishment is added to an instrumental bar-pressing paradigm, but only on one of the bars. Normal animals will adjust their bar-pressing away from this lever. (Note: These authors, however, implemented a punishment procedure by presenting a CS and shock upon bar-press, rather than a conditioned punishment procedure which would only present the CS upon bar-press). In conditioned reinforcement, a CS predicting reward is added to the instrumental bar-pressing paradigm on one of the bars. Animals will naturally come to favor this bar paired with the appetitive CS.
DA agonists increased the effect of a punishing CS, causing the animals to further decrease their bar pressing. DA agonists also enhanced the effect of an appetitive CS, increasing bar pressing. DA antagonists, on the other hand, decreased the effect of a punishing CS. They also reduced the effect of an appetitive CS. Thus, it appears dopaminergic agents modulate the behavioral impact of both appetitively and aversively motivated conditioned stimuli on instrumental performance. Systemic benzodiazepene administration was also explored with results showing a selective impact on aversively-motivated stimuli (i.e. no effect on the appetitive CS).
Monday, September 15, 2008
Hippocampal involvement in contextual modulaton of fear extinction
Ji, J. & Maren, S. (2007). Hippocampal involvement in contextual modulaton of fear extinction. Hippocampus, 17, 749-758.
Responding to an extinguished CS is susceptible to many recovery effects. The first is renewal, in which changing the context favors recall of extinguished fear memory. Examination of its several forms (ABA, AAB, ABC) led researchers to postulate that following extinction the meaning of the CS becomes ambiguous and requires context to disambiguate; inhibitory association is "gated" so that its activation requires the simultaneous presence of the CS and the extinction context. The second is spontaneous recovery, or the return of conditional responding with the passage of time. Studies suggest that renewal and spontaneous recovery appear to result from a similar control mechanism, rather than simply erasure of the original fear memory. Therefore, some see SR as another renewal effect that occurs outside of the "temporal extinction context". Third is reinstatement, in which the extinguished response returns after extinction if the animal is merely exposed to the US alone in a distinct context. This, likewise, appears to be a context-dependent process.
These all suggest that extinction involves new learning, and that this learning is especially sensitive to context. The hippocampus, mPFC, and amygdala have been implicated in this learning. One model holds that when the animal is tested within the extinction context, hippocampus drives mPFC inhibition of LA. When animals are presented with an extinguished CS outside of the extinction context, the hippocampus may inhibit mPFC activation and thus promote excitation in the LA to renew extinguished fear under these conditions. Another model posits direct projection from hippocampus to LA subserving contextual modulation of extinction.
Responding to an extinguished CS is susceptible to many recovery effects. The first is renewal, in which changing the context favors recall of extinguished fear memory. Examination of its several forms (ABA, AAB, ABC) led researchers to postulate that following extinction the meaning of the CS becomes ambiguous and requires context to disambiguate; inhibitory association is "gated" so that its activation requires the simultaneous presence of the CS and the extinction context. The second is spontaneous recovery, or the return of conditional responding with the passage of time. Studies suggest that renewal and spontaneous recovery appear to result from a similar control mechanism, rather than simply erasure of the original fear memory. Therefore, some see SR as another renewal effect that occurs outside of the "temporal extinction context". Third is reinstatement, in which the extinguished response returns after extinction if the animal is merely exposed to the US alone in a distinct context. This, likewise, appears to be a context-dependent process.
These all suggest that extinction involves new learning, and that this learning is especially sensitive to context. The hippocampus, mPFC, and amygdala have been implicated in this learning. One model holds that when the animal is tested within the extinction context, hippocampus drives mPFC inhibition of LA. When animals are presented with an extinguished CS outside of the extinction context, the hippocampus may inhibit mPFC activation and thus promote excitation in the LA to renew extinguished fear under these conditions. Another model posits direct projection from hippocampus to LA subserving contextual modulation of extinction.
Friday, September 5, 2008
Emotion Circuits in the Brain
LeDoux, J.E. (2000). Emotion Circuits in the Brain. Annual Reviews in Neuroscience, 23, 155-184.
Emotion research was largely lost for some time in the wake of the cognitive revolution. However, people soon realized a purely cognitive view of the brain -- leaving out emotions, motivations, and the like -- is likely to paint an unrealistic view of real minds. Unfortunately, attempts to dig into emotions once again were hamstrung by the limbic system concept, a flawed and inadequate theory of the emotional brain: cognition does not only reside in the neocortex and emotions do not only reside within the limbic system (a moving target itself).
Emotion research began its official resurgence with a bottoms-up examination of fear conditioning, with a bulk of the work focused on the auditory modality. Research soon named amygdala as centrally important, a site where transmission of information about the CS and US converged and output projections controlled fear reactions. On the input side, CS sensory inputs terminate in the lateral amygdala (LA), coming from both the auditory thalamus and the auditory cortex, although plasticity seems to occur initially through the thalamic pathway. US information also seems to converge in the amygdala, receiving inputs from the spino-thalamic tract, cortical areas that process somatosensory stimuli including nociceptive stimuli, the parabrachial area, and the spinal cord. On the outbound side, the central nucleus of the amygdala (CE) projects to autonomic (hypothalamus) and defensive motoric (periaqueductal gray) centers. Methodologies used have largely been single unit recordings, long-term potentiation (LTP) studies, and pharmacological experiments which block LTP. Studies have focused on two types of fear learning: simple fear conditioning (a benign tone comes to evoke a fear response) and contextual fear conditioning (fear responsivity to environmental cues). Research agrees that the amygdala seems to be required for Pavlovian fear conditioning to occur, although the site of long-term fear memory storage is still unknown: it may very well exist in the amygdala, but it may also be distributed across multiple structures or transferred off to cortical areas over time. However, plasticity within the amygdala is probably not required for learning cognitive aspects of fear.
Human studies have echoed many of the results from animal literature. Additionally, they have found perceptual deficits of the emotional meaning of faces in patients with amygdalar damage. The amygdala also appears activated more strongly in the presence of fearful and angry faces than of happy ones. Further, when the activity of the amygdala during fear conditioning is cross-correlated with other regions of the brain, the strongest relations are seen in subcortical areas, emphasizing the importance of the direct thalamo-amygdala pathway in the human brain. Although a fear conditioning approach cannot account for all aspects of human fear and anxiety disorders, it may be especially elucidating for PTSD, panic disorders, and phobias. Difficulty in extinguishing fear memories witnessed in human disorders may also involve the medial prefrontal cortex circuitry.
Future research needs to integrate both cognition and emotion. How fear processing in the amygdala can influence perceptual, attentional, and memory functions of the cortex, and vice versa, is begging for additional research, although it is known that the amygdala does receive input from cortical sensory processing regions and projects back to these both directly and indirectly. How conscious emotional feelings are manifest is also relatively unexplored, although the models posit that feelings may arise from interactions between the amygdala and prefrontal working memory areas, sensory processing areas in cortex, long-term memory systems in the temportal lobe, and arousal systems which maintain global projections.
Saturday, February 16, 2008
Direct and indirect activation effects on reconsolidation in amygdala
Debiec, J., Doyere, V., Nader, K., LeDoux, J.E. (February 28, 2006). Directly reactivated, but not indirectly reactivated, memories undergo reconsolidation in the amygdala. PNAS, Volume 103, Number 9, 3428-3433.
The first experiment of the paper used second-order fear conditioning (SOFC) to create an associative memory network in rat brain. To do this, a conditioned stimulus (CS1) is paired with an unconditioned stimulus (US), which naturally elicits a response. After pairing, now CS1 elicits the response (such as freezing in fear). This is the first-order conditioning. Now, a second conditioned stimulus (CS2) is paired with CS1, and by association elicits the response transitively. When extinction of CS1 responding does not affect the responding of CS2, CS2 is considered independent of the first-order fear memory. But if CS2 responding decreases with CS1 extinction, then we have an associative chain (CS2 --> CS1 --> US).
The second experiment, building on such a conditioning chain, discovered that extinction of freezing responses to the first-order stimulus (CS1) leads to responding impairments in CS2. Extinction of the second-order stimulus (CS2), does not have any effect on CS1. This builds a case for a hierarchical, uni-directional chain.
The last experiment examined the effect of activation (memory retrieval) on such an associative chain. (In another paper, Nader and LeDoux showed that reactivation of a memory places it in a labile state -- that is, susceptible to disruption -- until again reconsolidated.) Results demonstrated that protein synthesis inhibition after exposure to a single CS1 impairs responses to both CS1 and CS2. But protein synthesis inhibition after exposure to a single CS2, only disrupts CS2 and leaves CS1 freezing intact. Therefore, it is believed that when the first-order association is directly activated, it is placed into a labile state, which may have an impact on dependent associations. However, when the first-order association is only indirectly activated (through an associative chain), it appears that there is not sufficient stimulation to kick off cellular processes which would place it in a labile state, so it remains fixed.
Clinical applications of such research may be in the areas of PTSD, where victims suffer not only from fearful memories, but also from everyday stimuli somehow associated with the initial trauma. This study shows that disrupting associated reactions will only alleviate the sufferer from these quirky stress reactions, while breaking associative chains at the root cause may provide cascading relief.
The first experiment of the paper used second-order fear conditioning (SOFC) to create an associative memory network in rat brain. To do this, a conditioned stimulus (CS1) is paired with an unconditioned stimulus (US), which naturally elicits a response. After pairing, now CS1 elicits the response (such as freezing in fear). This is the first-order conditioning. Now, a second conditioned stimulus (CS2) is paired with CS1, and by association elicits the response transitively. When extinction of CS1 responding does not affect the responding of CS2, CS2 is considered independent of the first-order fear memory. But if CS2 responding decreases with CS1 extinction, then we have an associative chain (CS2 --> CS1 --> US).
The second experiment, building on such a conditioning chain, discovered that extinction of freezing responses to the first-order stimulus (CS1) leads to responding impairments in CS2. Extinction of the second-order stimulus (CS2), does not have any effect on CS1. This builds a case for a hierarchical, uni-directional chain.
The last experiment examined the effect of activation (memory retrieval) on such an associative chain. (In another paper, Nader and LeDoux showed that reactivation of a memory places it in a labile state -- that is, susceptible to disruption -- until again reconsolidated.) Results demonstrated that protein synthesis inhibition after exposure to a single CS1 impairs responses to both CS1 and CS2. But protein synthesis inhibition after exposure to a single CS2, only disrupts CS2 and leaves CS1 freezing intact. Therefore, it is believed that when the first-order association is directly activated, it is placed into a labile state, which may have an impact on dependent associations. However, when the first-order association is only indirectly activated (through an associative chain), it appears that there is not sufficient stimulation to kick off cellular processes which would place it in a labile state, so it remains fixed.
Clinical applications of such research may be in the areas of PTSD, where victims suffer not only from fearful memories, but also from everyday stimuli somehow associated with the initial trauma. This study shows that disrupting associated reactions will only alleviate the sufferer from these quirky stress reactions, while breaking associative chains at the root cause may provide cascading relief.
Tuesday, January 15, 2008
The Amygdala
LeDoux, J. (October 2007). The amygdala, Current Biology, Vol. 17, R868-R874.
This is a fantastic overview of a very important brain structure by one of the world's leading experts on the subject. The article covers the amygdala's anatomic organization (its different nuclei), its connectivity (both inputs and outputs), its cellular mechanisms (neurotransmission and neuromodulation), its role in emotional processing, and its implication in a variety of human disorders. The article even covers neuronal processes related to classical conditioning (i.e. fear memory consolidation and reconsolidation), such as changes in synaptic strength (upregulation of post-synaptic receptors by LTP), structural changes in synaptic connectivity (post-synaptic cytoskeletal alterations, presumably dendritic and microtubule changes), and pre-synaptic feedback mechanisms (release of nitric oxide as a messenger).
This is a fantastic overview of a very important brain structure by one of the world's leading experts on the subject. The article covers the amygdala's anatomic organization (its different nuclei), its connectivity (both inputs and outputs), its cellular mechanisms (neurotransmission and neuromodulation), its role in emotional processing, and its implication in a variety of human disorders. The article even covers neuronal processes related to classical conditioning (i.e. fear memory consolidation and reconsolidation), such as changes in synaptic strength (upregulation of post-synaptic receptors by LTP), structural changes in synaptic connectivity (post-synaptic cytoskeletal alterations, presumably dendritic and microtubule changes), and pre-synaptic feedback mechanisms (release of nitric oxide as a messenger).
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