Chapter 20. Learning and Memory: Basic Mechanisms Copyright © 2014 Elsevier Inc. All rights...

Chapter 20. Learning and Memory: Basic Mechanisms

Copyright © 2014 Elsevier Inc. All rights reserved

Figure 20.1 Classical conditioning.In the procedure introduced by Pavlov, the production of saliva is monitored continuously. Presentation of meat powder reliably leads to salivation, whereas some “neutral” stimulus such as a bell initially does not. With repeated pairings of the bell and meat powder, the animal learns that the bell predicts the food and salivates in response to the bell alone.Modified from Rachlin (1991).


Figure 20.2 Siphon–gill and tail–siphon withdrawal reflexes of Aplysia.(A) Siphon–gill withdrawal. Dorsal view of Aplysia: (1) Relaxed position. (2) A stimulus (e.g., a water jet, brief touch, or weak electric shock) applied to the siphon causes the siphon and the gill to withdraw into the mantle cavity. (B) Tail–siphon withdrawal reflex: (1) Relaxed position. (2) A stimulus applied to the tail elicits a reflex withdrawal of the tail, the siphon, and the gill.


Figure 20.3 Simplified circuit diagrams of the siphon–gill (A) and tail–siphon (B) withdrawal reflexes.Stimuli activate the afferent terminals of mechanoreceptor sensory neurons (SN), the somata of which are located in central ganglia (abdominal and pleural). The sensory neurons make excitatory synaptic connections (triangles) with interneurons (IN) and motor neurons (MN). The excitatory interneurons provide a parallel pathway for excitation of the motor neurons. Action potentials elicited in the motor neurons, triggered by the combined input from the SNs and INs, propagate out peripheral nerves to activate muscle cells and produce the subsequent reflex withdrawal of the organs. Modulatory neurons (not shown here but see Fig. 20.4A), such as those containing serotonin (5-HT), regulate the properties of the circuit elements and, consequently, the strength of the behavioral responses.


Figure 20.4 Model of short-term heterosynaptic facilitation of the sensorimotor connection that contributes to short-term sensitization in Aplysia.(A) Sensitizing stimuli activate facilitatory interneurons (IN) that release modulatory transmitters, one of which is 5-HT. The modulator leads to an alteration of the properties of the sensory neuron (SN). (B1, B2) An action potential in SN after the sensitizing stimulus results in greater transmitter release and hence a larger postsynaptic potential in the motor neuron (MN, B2) than an action potential before the sensitizing stimulus (B1). For short-term sensitization, the enhancement of transmitter release is due, at least in part, to broadening of the action potential and an enhanced flow of Ca2+ into the sensory neuron.


Figure 20.5 Model of classical conditioning of a withdrawal reflex in Aplysia.(A) Activity in a sensory neuron (SN1) along the CS+ (paired) pathway is coincident with activity in neurons along the reinforcement pathway (US). However, activity in the sensory neuron (SN2) along the CS− (unpaired) pathway is not coincident with activity in neurons along the US pathway. The US directly activates the motor neuron, producing the UR. The US also activates a modulatory system in the form of the facilitatory neuron, resulting in the delivery of a neuromodulatory transmitter to the two sensory neurons. The pairing of activity in SN1 with the delivery of the neuromodulator yields the associative modifications. (B) After the paired activity in (A), the synapse from SN1 to the motor neuron is selectively enhanced. Thus, it is more likely to activate the motor neuron and produce the conditioned response (CR) in the absence of US input.Modified from Lechner and Byrne (1998).


Figure 20.6 Model of associative facilitation at the Aplysia sensorimotor synapse.This model has both a presynaptic and a postsynaptic detector for the coincidence of the CS and the US. Furthermore, a putative retrograde signal allows for the integration of these two detection systems at the presynaptic level. The CS leads to activity in the sensory neuron, yielding presynaptic calcium influx, which enhances the US-induced cAMP cascade. The CS also induces glutamate release, which results in postsynaptic calcium influx through NMDA receptors if paired with the US-induced depolarization of the postsynaptic neuron. The postsynaptic calcium influx putatively induces a retrograde signal, which further enhances the presynaptic cAMP cascade. The end result of the cAMP cascade is to modulate transmitter release and enhance the strength of the synapse.Modified from Lechner and Byrne (1998).


Figure 20.7 Operant conditioning of feeding behavior.Throughout the experiment, the animal was observed and all bites were recorded. In the contingent reinforcement group, a bite was immediately followed by a brief electric stimulation of the esophageal nerve. A control group received the same sequence of stimulations as the contingent group, but the stimulation was uncorrelated with the animal’s behavior. Experimental sessions consisted of a 5-min pretest, 10 min of training, and a final test period. In each period, the number of bites was recorded. The final test period was either 1 or 24 h after training. The group of animals that received contingent reinforcement showed a significantly larger number of spontaneous bites both 1 and 24 h after training compared with control animals.Modified from Brembs et al. (2002).


Figure 20.8 Changes in B51 produced by single-cell in vitro analog of operant conditioning.Contingent-dependent changes in burst threshold and input resistance in cultured B51. (A) Burst threshold. (A1, A2) Intracellular recordings from a pair of contingently reinforced and unpaired neurons. Depolarizing current pulses were injected into B51 before (Pre-test) and after (Post-test) training. In this example, contingent reinforcement led to a decrease in burst threshold from 0.8 to 0.5 nA (A1), whereas it remained at 0.7 nA in the corresponding unpaired cell (A2). (A3) Summary data. The contingently reinforced cells had significantly decreased burst thresholds. (B) Input resistance. (B1, B2) Intracellular recordings from a pair of contingently reinforced and unpaired control neurons. Hyperpolarizing current pulses were injected into B51 before (Pre-test) and after (Post-test) training. In this example, contingent reinforcement led to an increased deflection of the B51 membrane potential in response to the current pulse (B1), whereas the deflection remained constant in the corresponding unpaired cell (B2). (B3) Summary data. The contingently reinforced cells had significantly increased input resistances. Modified fromBrembs et al. (2002). (C) Model of the molecular mechanisms underlying operant conditioning. See text for details.Modified from Lorenzetti et al. (2008).


Figure 20.9 Adaptive nature of classical conditioning.This example shows the development of the conditioned eyelid response over the trials of training. The CS is typically a “neutral” light or tone; the US here is a puff of air to the cornea. The eyelid closure response is indicated by upward movement of the tracing. The first marker is tone CS onset; the second is air puff US onset. In trial 1 the eyelid does not move to the CS but closes (blinks) following onset of the US. The conditioned response (CR) is any measurable degree of eyelid closure prior to the onset of the US. Note that after learning, the CR peaks at the onset of the US, that is, maximum eyelid closure at air puff onset. If the CS–US onset interval were longer (e.g., 500 ms), the CR would now peak at the onset of the US, 500 ms after CS onset. The conditioned response is adaptive. For this type of learning, a period (ISI) of about 250 ms between CS onset and US onset (shown here) yields the best learning. This best learning time varies widely depending on the type of response (e.g., for fear learning, several seconds is best).


Figure 20.10 Simplified schematic of the essential brain circuitry involved in standard delay classical conditioning of discrete responses (e.g., eyelid response).Shadowed boxes represent areas that have been reversibly inactivated during training. (a) Inactivation of motor nuclei including facial (seventh) and accessory sixth. (b) Inactivation of magnocellular red nucleus. (c) Inactivation of dorsal aspect of the anterior interpositus and overlying cerebellar cortex. (d) Inactivation localized to the anterior interpositus nucleus (heavy shading entirely within the nucleus), (e) Complete inactivation of the superior cerebellar peduncle (scp), all output from the interpositus nucleus. Inactivation of each of these regions in trained rabbits abolishes performance of the CR. Significantly, inactivation of the motor nuclei (a), the red nucleus (b), and the output from the nucleus, the superior cerebellar peduncle (e), during training do not prevent learning at all, but inactivation of a localized region of the anterior interpositus nucleus (d) during training completely prevents learning.


Figure 20.11 Engagement of neurons in the cerebellar interpositus nucleus in eyelid conditioning.Histograms of a unit cluster recording from the anterior interpositus nucleus over the course of training are shown. The eyelid response (here nictitating membrane extension) is shown on the tracing above each histogram. (A) Results of a day of unpaired CS and US presentations. There is some activity in response to the US. However, when paired training (B) is given (days 1 and 2), as behavioral learning develops (eyelid closure prior to US onset) there is a massive increase in neuronal discharges in the CS period that precedes and correlates with performance of the conditioned eyeblink response. Total trace duration, 750 ms; CS–US onset interval, 250 ms. Each trace and histogram is the average or cumulation of 1 day of training (120 trials).From McCormick and Thompson (1984).


Figure 20.12 Functional localization of brain cerebellar activity (PET scan) in human eyelid conditioning.The cerebellar anterior interpositus nucleus and several regions of cerebellar cortex show highly significant increases in activation with learning.From Logan and Grafton (1995).


Figure 20.13 Commonly accepted eyelid conditioning circuit based on experimental findings and anatomy of the cerebellum and the brain stem.The conditioned stimulus (CS) pathway consists of excitatory (+) mossy fiber (MF) projections primarily from the pontine nuclei (PN) to the interpositus nucleus (Int) and to the cerebellar cortex. In the cortex, the mossy fibers form synapses with granule cells (GR), which in turn send excitatory parallel fibers to the Purkinje cells (PC). Purkinje cells are the exclusive output neurons from the cortex, and they send inhibitory (−) fibers to deep nuclei such as the interpositus. The unconditioned stimulus (US) pathway consists of excitatory climbing fiber (CF) projections from the inferior olive (IO) to the interpositus nucleus and to the Purkinje cells in the cerebellar cortex. Within the cerebellar cortex, Golgi (GO), stellate (ST), and basket (BA) cells exert inhibitory actions on their respective target neurons. The efferent conditioned response (CR) pathway projects from the interpositus nucleus to the red nucleus (RN) and via the descending rubral pathway to act ultimately on the motor neurons generating the eyeblink response. V Coch N, ventral cochlear nucleus; N V (sp), spinal fifth cranial nucleus; N VI, sixth and accessory sixth cranial nuclei; N VII, seventh cranial nucleus; UR, unconditioned response. Note that the reflex pathways do not involve the cerebellar circuitry. Note also the inhibitory projection from the interpositus (Int) to the inferior olive (IO).From Kim and Thompson (1997).


Figure 20.14 The climbing fiber (CF) pathway and associative motor learning.(A) Schematic of the proposed sites (colored bursts) within the cerebellar circuit where CFs might “teach” during associative motor learning. The blue burst denotes CF driven LTD of parallel fibers (PFs), while the red bursts denote CF driven LTP of either PF inputs (at MLI—inhibitory interneurons) or mossy fiber (MF) inputs at the cerebellar nuclei, e.g., interpositus (DCN). Terminal arrowheads indicate excitatory connections and dots inhibitory connections. (B) ChR2-eYFP expressing CFs are visible in this multi-photon microscope image of part of folia X in a 300 μm thick rat brain slice.From Otis et al. (2012).


Figure 20.15 Engagement of hippocampal neurons in eyelid conditioning.Responses of identified pyramidal neurons during paired (A, B) and unpaired (C–F) presentations of tone and corneal air puff. The upper traces show the averaged nictitating membrane (NM, a component of the eyelid) response for all trials during which a given cell was recorded. The bottom traces show the response of the recorded neuron in the form of a peristimulus time histogram. The total length of both NM responses and histograms was 750 ms. Arrows occurring early in the trial period indicate tone onset; arrows occurring late in the trial period indicate air puff onset. H, hippocampus. In this particular figure, A and B show examples of responses of two pyramidal neurons recorded from two different animals during delay conditioning. The results in C and E show the response of a pyramidal neuron recorded from an animal given unpaired tone alone (C) and air puff alone (E) presentations. (D, F) Same for a different pyramidal cell recorded from a different control animal.From Berger et al. (1986).


Figure 20.16 Effects of hippocampal lesions on retention of trace CRs.Shown are the mean percentage of adaptive CRs during initial training and following postoperative training: 1 day cont, controls given cortical or sham lesions 1 day after training; 1 month cont, controls given lesions 1 month after training; 1 day hipp, bilateral hippocampal lesions made 1 day after training; 1 month hipp, hippocampal lesions made 1 month after training. Only the hippocampal lesions made immediately after training abolished the trace CR.From Kim et al. (1995).


Figure 20.17 Hippocampal CA1 pyramidal cells (intracellular recordings) exhibit a transient increase in excitability following acquisition of trace eyeblink conditioning.(A) Overlapping traces of AHPs in CA1 neurons following injection of a 100 ms depolarizing current (horizontal bar). Current injection was the minimum required to elicit burst of four action potentials and did not differ significantly between groups. Amplitude and duration of AHP is similar in recordings from animals not exposed to training stimuli (naïve) and recordings from animals 14 d after acquisition (retention). Recordings from pyramidal cells 24 h following acquisition show a significant decrease in the duration and amplitude of the AHP (trace 24 h). (B) Spike accommodation in response to 800 ms depolarizing current is significantly reduced in CA1 pyramidal neurons 24 h after acquisition (trace 24 h) as compared with pyramidal cells from animals receiving explicitly unpaired stimuli presentations (pseudo) or animals trained 14 d prior to recording.From Moyer et al. (1996).


Figure 20.18 A schematic of the connections that might mediate trace eyelid conditioning.Here the CS is somatosensory (whisker movement). For a tone CS the medial geniculate nucleus and auditory cortex would replace the VPM and somatosensory cortex. The pontine nuclei are indicated as the critical node between the forebrain and the cerebellum and the thalamic nuclei are shown as the interface between the cerebellum and the different cortical regions. The authors also hypothesize which parts of the circuit are more related to declarative memory and which parts are more related to working memory. The hippocampus is shown at an intersection of the two processes. (The circuitry for these two processes is not yet confirmed). SI and SII: primary and secondary somatosensory ciortex; VPM: ventral posterior medial thalamus; cAC: caudal anterior cingulated: rAC: rostral anterior cingulate; PL: prelimbic cortex; dlPFC: dorsolateral prefrontal cortex; AV: anteroventral thalamus; VA: ventral anterior thalamus; MD: dorsomedial thalamus; HF: hippocampal formation; BG: basal ganglia; RNm: magnocellular red nucleus; rDAO: rostral dorsal accessory olive; MNs: motor neurons; V: trigeminal nucleus; EC/PC: entorhinal/perirhinal cortex; ZI: zona incerta; RNpc: parvicellular red nucleus.From Weiss and Disterhoft (2011).


Figure 20.19 Fear conditioning paradigm:(A) Typical parametric arrangement of stimuli during the acquisition and extinction phases of a simple delay conditioning task. CS, conditioned stimulus; US, unconditioned stimulus. (B) Hypothetical (but realistic) acquisition and extinction learning curves for defense (freezing) responses conditioned to the CS. Note the rapid increase of freezing during the CS during acquisition trials (A1–A3) and the decline of freezing during extinction trials (E1–E3).


Figure 20.20 CS and US transmission pathways in fear conditioning.The auditory conditioned stimulus and somatosensory unconditioned stimulus are transmitted through brainstem to the thalamic stations in each pathway. The thalamic regions give rise to connections to cortical receiving areas. Components of both the thalamic and cortical processing regions in each pathway then connect with the lateral nucleus of the amygdala. Brain lesion studies suggest that the CS and US can reach the amygdala through either thalamic or cortical areas.


Figure 20.21 Model of synaptic plasticity during fear conditioning.The CS provides weak glutamate-mediated activation of presynaptic inputs to lateral amygdala cells. The glutamate activates AMPA receptors but cannot activate NMDA receptors in the absence of strong, depolarizing inputs to the cell. If the weak presynaptic input from the CS arrives at about the same time that the postsynaptic cell is depolarized by a strong input, such as by the US, postsynaptic depolarization occurs, allowing calcium to enter through NMDA receptors and voltage-gated calcium channels (VGCCs). This combined calcium signal then activates a variety of signaling pathways, including MAPK, PKA, and CREB, and initiates RNA and protein synthesis. The proteins then act at the CS input synapses to strengthen and stabilize the connection.


Figure 20.22 Neural circuits for conditioned fear learning in humans.(A) A summary of nine studies showing hemodynamic changes in the amygdala and adjacent periamygdaloid cortex, thalamus, and anterior cingulate/dorsomedial prefrontal cortex of healthy human adults during conditioned fear learning. (B) Damage to the amygdala versus hippocampus yields dissociable deficits during conditioned fear learning. Whereas a patient with selective bilateral amygdala damage (SM) has intact declarative memory for a conditioning episode, she fails to acquire conditioned skin conductance responses (SCR) to visual or auditory conditioned stimuli. In contrast, a patient with selective bilateral hippocampal damage (WC) shows the reverse pattern. Healthy controls acquire both conditioned SCRs and declarative knowledge, presumably via the distinct influences of these brain regions. μS=microsiemens.Adapted from LaBar and Cabeza (2006).


Figure 20.23 Autoassociation network for recognition memory.The artificial circuit consists of six input pathways that make strong connections to each of six output neurons. The output neurons have axon collaterals that make synaptic connections with each of the output cells. (A) A pattern represented by activity in the input lines or axons (a, b, c, d, e, f) is presented to the network. A 1 represents an active axon (e.g., a spike) whereas a 0 represents an inactive axon. The input pathways make strong synapses (filled circles) with the postsynaptic output cells. Thus, the output cells (u, v, w, x, y, z) generate a pattern that is a replica of the input pattern. The collateral synapses were initially weak and do not contribute to the output. Nevertheless, the activity in the collaterals that occurred in conjunction (assume minimal delays within the circuit) with the input pattern led to a strengthening of a subset of the 36 synapses. (B) A second presentation of the input produces an output pattern that is an amplified, but otherwise intact, replica of the input. An incomplete input pattern can be used as a cue to retrieve the complete pattern.


Chapter 20. Learning and Memory: Basic Mechanisms Copyright © 2014 Elsevier Inc. All rights...

Documents

Transcript of Chapter 20. Learning and Memory: Basic Mechanisms Copyright © 2014 Elsevier Inc. All rights...