NMDA and muscarinic receptors of the nucleus accumbens have differential effects on taste memory formation

Animals recognize a taste cue as aversive when it has been associated with post-ingestive malaise; this associative learning is known as conditioned taste aversion (CTA). When an animal consumes a new taste and no negative consequences follow, it becomes recognized as a safe signal, leading to an increase in its consumption in subsequent presentations (attenuation of neophobia, AN). It has been shown that the nucleus accumbens (NAcc) has an important role in taste learning. To elucidate the involvement of N-methyl-D-aspartate (NMDA) and muscarinic receptors in the NAcc during safe and aversive taste memory formation, we administrated bilateral infusions of DL-2-amino-5-phosphonopentanoic acid (APV) or scopolamine in the NAcc shell or core respectively. Our results showed that pre-training injections of APV in the NAcc core and shell disrupted aversive but not safe taste memory formation, whereas pre-training injections of scopolamine in the NAcc shell, but not core, disrupted both CTA and AN. These results suggest that muscarinic receptors seem to be necessary for processing taste stimuli for either safe or aversive taste memory, whereas NMDA receptors are only involved in the aversive taste memory trace formation.     

Role of cholinergic system on the construction of memories: taste memory encoding

There is a large body of evidence suggesting that cholinergic activity is involved in memory processes. It seems that cholinergic activity is essential to learn several tasks and recent works suggest that acetylcholine plays an important role during the early stages of memory formation. In this review, we will discuss the results related to taste memory formation, focusing particularly on the conditioned taste aversion paradigm. We will first give evidence that nucleus basalis magnocellularis is involved in taste memory formation, due to its cholinergic projections. We then show that the cholinergic activity of the insular (gustatory) cortex is related to the taste novelty, and that the cholinergic signals initiated by novelty are crucial for taste memory formation. Then we present recent data indicating that cortical activation of muscarinic receptors is necessary for taste trace encoding, and also for its consolidation under certain circumstances. Finally, interactions between the cholinergic and other neuromodulatory systems inducing intracellular mechanisms related to plastic changes will be proposed as important processes underlying gustatory memory trace storage.     

Contributions of glucocorticoid receptors in cortical astrocytes to memory recall

Dysfunctions in memory recall lead to pathological fear; a hallmark of trauma-related disorders, like posttraumatic stress disorder (PTSD). Both, heightened recall of an association between a cue and trauma, as well as impoverished recall that a previously trauma-related cue is no longer a threat, result in a debilitating fear toward the cue. Glucocorticoid-mediated action via the glucocorticoid receptor (GR) influences memory recall. This literature has primarily focused on GRs expressed in neurons or ignored cell-type specific contributions. To ask how GR action in nonneuronal cells influences memory recall, we combined auditory fear conditioning in mice and the knockout of GRs in astrocytes in the prefrontal cortex (PFC), a brain region implicated in memory recall. We found that knocking out GRs in astrocytes of the PFC disrupted memory recall. Specifically, we found that knocking out GRs in astrocytes in the PFC (AstroGRKO) after fear conditioning resulted in higher levels of freezing to the CS+ tone when compared with controls (AstroGRintact). While we did not find any differences in extinction of fear toward the CS+ between these groups, AstroGRKO female but not male mice showed impaired recall of extinction training. These results suggest that GRs in cortical astrocytes contribute to memory recall. These data demonstrate the need to examine GR action in cortical astrocytes to elucidate the basic neurobiology underlying memory recall and potential mechanisms that underlie female-specific biases in the incidence of PTSD.

Recalling important information about salient environmental cues is an integral part of how we navigate our world. Recalling too much, or too little, information about salient environmental cues is a part of the psychopathology of posttraumatic stress disorder (PTSD) (Milad and Quirk 2012). More specifically, the augmented recall of an association between an environmental cue and a traumatic event results in debilitating fear toward the cue, even in the absence of any threat. In contrast, impoverished recall of information that a cue, previously associated with trauma, is no longer a threat also results in debilitating fear toward the cue after it is no longer dangerous. Therefore, one way to mitigate debilitating fear that characterizes PTSD is to understand the neurobiological mechanisms underlying memory recall.Among many mechanisms, glucocorticoid action via signaling through glucocorticoid receptors (GRs) is an important neurobiological pathway that underlies the recall of salient information. When trauma-associated cues are encountered, the hypothalamic-pituitary-adrenal axis is activated and GR signaling is consequently triggered (McEwen et al. 1988; McEwen 1992; Lupien et al. 2009). Existing literature demonstrates that glucocorticoids and GRs do in fact influence learning, memory, and the recall of learning (Pugh et al. 1997; de Quervain et al. 1998, 2009, 2011, 2017, 2019; Roozendaal 2002, 2003; Conrad et al. 2004; Hui et al. 2004; Donley et al. 2005; Roozendaal and de Quervain 2005; Cai et al. 2006; Soravia et al. 2006; Yang et al. 2006; Roozendaal et al. 2009; Bentz et al. 2010; Blundell et al. 2011; Clay et al. 2011; Nikzad et al. 2011; Roesler 2012; Liao et al. 2013; Wislowska-Stanek et al. 2013; Arp et al. 2016; Reis et al. 2016; Dadkhah et al. 2018; Inoue et al. 2018; Scheimann et al. 2019; Lin et al. 2020). The relationship between glucocorticoids, GRs, learning and memory is complicated and within the literature cited above, one can find examples of GR action being facilitatory as well as inhibitory to learning and memory recall. As expansive as this research is, the influence of GRs on learning, memory, and recall of learning has mostly focused only on GR action in neurons or has ignored cell type specific contributions. While glia are approximately as common as neurons in the nervous system (von Bartheld et al. 2016; von Bartheld 2018), the role of GRs in glial cells on the recall of salient environmental cues has been neglected. More specifically, while astrocytes comprise a significant proportion of the glial cell population (von Bartheld et al. 2016) and express GRs (Vielkind et al. 1990; Bohn et al. 1991), the influence of GRs in astrocytes on memory recall remains largely unappreciated (for one exception, see the Discussion).Our goal in this study was to determine the influence of GRs in astrocytes on memory recall. To do so, we combined the robust and reliable experimental framework of classical fear conditioning in rodents (Santini et al. 2008; Dias et al. 2014; Bukalo et al. 2015; Keiser et al. 2017; Giustino and Maren 2018; Greiner et al. 2019; Gunduz-Cinar et al. 2019; Venkataraman et al. 2019) with molecular genetic manipulations in the prefrontal cortex (PFC), a brain region critical for the recall of memory (Morgan and LeDoux 1995; Quirk et al. 2000; Mueller et al. 2008; Quirk and Mueller 2008; Giustino and Maren 2015; Rozeske et al. 2015; Maren and Holmes 2016). We first trained mice to associate tone presentations with mild footshocks. After this auditory fear conditioning, we used a CRE-loxP strategy to specifically knock out GRs in astrocytes in the PFC (hereafter termed cortical astrocytes) of these trained mice. We then exposed animals to extinction training: 30 presentations of the tone in the absence of any footshocks. Finally, 1 d after the extinction training, we exposed animals to two presentations of the tone. This experimental timeline allowed us to ask how a lack of GRs in cortical astrocytes influences (1) the recall of the previous aversive association of the tone presentation with the footshock, (2) the extinction of fear that would typically occur during extinction training, and (3) the recall of extinction training allowing us to measure the influence of GRs in cortical astrocytes on the recall of extinction training. Broadly, our results demonstrate that knocking out GRs in cortical astrocytes disrupts fear memory recall in both male and female mice, while only disrupting extinction recall in female mice.     

Perirhinal cortex muscarinic receptor blockade impairs taste recognition memory formation

The relevance of perirhinal cortical cholinergic and glutamatergic neurotransmission for taste recognition memory and learned taste aversion was assessed by microinfusions of muscarinic (scopolamine), NMDA (AP-5), and AMPA (NBQX) receptor antagonists. Infusions of scopolamine, but not AP5 or NBQX, prevented the consolidation of taste recognition memory using attenuation of neophobia as an index. In addition, learned taste aversion in both short- and long-term memory tests was exclusively impaired by scopolamine. These data provide neurochemical support for the theory that cholinergic activity of the perirhinal cortex participates in the formation of the taste memory trace and that it is independent of the NMDA and AMPA receptor activity. These results support the idea that cholinergic neurotransmission in the perirhinal cortex is also essential for acquisition and consolidation of taste recognition memory.     

The role of metabotropic glutamate receptors and cortical adaptation in habituation of odor-guided behavior

Decreases in behavioral investigation of novel stimuli over time may be mediated by a variety of factors including changes in attention, internal state, and motivation. Sensory cortical adaptation, a decrease in sensory cortical responsiveness over prolonged stimulation, may also play a role. In olfaction, metabotropic glutamate receptors on cortical afferent pre-synaptic terminals have been shown to underlie both cortical sensory adaptation and habituation of odor-evoked reflexes. The present experiment examined whether blockade of sensory cortical adaptation through bilateral infusion of the group III metabotropic glutamate receptor antagonist cyclopropyl-4-phosphonophenylglycine (CPPG) into the anterior piriform cortex could reduce habituation of a more complex odor-driven behavior such as investigation of a scented object or a conspecific. The results demonstrate that time spent investigating a scented jar, or a conspecific, decreases over the course of a continuous 10 minute trial. Acute infusion of CPPG bilaterally into the anterior piriform cortex significantly enhanced the time spent investigating the scented jar compared to investigation time in control rats, without affecting overall behavioral activity levels. Infusions into the brain outside of the piriform cortex were without effect. CPPG infusion into the piriform cortex also produced an enhancement of time spent investigating a conspecific, although this effect was not significant.     

Superior formation of cortical memory traces for melodic patterns in musicians

The human central auditory system has a remarkable ability to establish memory traces for invariant features in the acoustic environment despite continual acoustic variations in the sounds heard. By recording the memory-related mismatch negativity (MMN) component of the auditory electric and magnetic brain responses as well as behavioral performance, we investigated how subjects learn to discriminate changes in a melodic pattern presented at several frequency levels. In addition, we explored whether musical expertise facilitates this learning. Our data show that especially musicians who perform music primarily without a score learn easily to detect contour changes in a melodic pattern presented at variable frequency levels. After learning, their auditory cortex detects these changes even when their attention is directed away from the sounds. The present results thus show that, after perceptual learning during attentive listening has taken place, changes in a highly complex auditory pattern can be detected automatically by the human auditory cortex and, further, that this process is facilitated by musical expertise.     

Cholinergic dependence of taste memory formation: evidence of two distinct processes

Learning the aversive or positive consequences associated with novel taste solutions has a strong significance for an animal's survival. A lack of recognition of a taste's consequences could prevent ingestion of potential edibles or encounter death. We used conditioned taste aversion (CTA) and attenuation of neophobia (AN) to study aversive and safe taste memory formation. To determine if muscarinic receptors in the insular cortex participate differentially in both tasks, we infused the muscarinic antagonists scopolamine at distinct times before or after the presentation of a strong concentration of saccharin, followed by either an i.p. injection of a malaise-inducing agent or no injection. Our results showed that blockade of muscarinic receptors before taste presentation disrupts both learning tasks. However, the same treatment after the taste prevents AN but not CTA. These results clearly demonstrate that cortical cholinergic activity participates in the acquisition of both safe and aversive memory formation, and that cortical muscarinic receptors seem to be necessary for safe but not for aversive taste memory consolidation. These results suggest that the taste memory trace is processed in the insular cortex simultaneously by at least two independent mechanisms, and that their interaction would determine the degree of aversion or preference learned to a novel taste.     

Blockade of nucleus basalis magnocellularis or activation of insular cortex histamine receptors disrupts formation but not retrieval of aversive taste memory

Recent research, using several experimental models, demonstrated that the histaminergic system is clearly involved in memory formation. This evidence suggested that during different associative learning tasks, histamine receptor subtypes have opposite functions, related to the regulation of cortical cholinergic activity. Given that cortical cholinergic activity and nucleus basalis magnocellularis (NBM) integrity are needed during taste memory formation, the aim of this study was to determine the role of histamine receptors during conditioned taste aversion (CTA). We evaluated the effects of bilateral infusions of 0.5 μl of pyrilamine (100 mM), an H₁ receptor antagonist, into the NBM, or of R-α-methylhistamine (RAMH) (10 mM), an H₃ receptor agonist, into the insular cortex of male Sprague-Dawley rats 20 min before acquisition and/or retrieval of conditioned taste aversion. The results showed that blockade of H₁ receptors in NBM or activation of H₃ receptors in the insular cortex impairs formation but not retrieval of aversive taste memory. These results demonstrated differential roles for histamine receptors in two important areas for taste memory formation and suggest that these effects could be related with the cortical cholinergic activity modulation during CTA acquisition.     

Critical role of the cholinergic system for object-in-place associative recognition memory

Object-in-place memory, which relies on the formation of associations between an object and the place in which it was encountered, depends upon a neural circuit comprising the perirhinal (PRH) and medial prefrontal (mPFC) cortices. This study examined the contribution of muscarinic cholinergic neurotransmission within this circuit to such object-in-place associative memory. Intracerebral administration of scopolamine in the PRH or mPFC impaired memory acquisition, but not retrieval and importantly we showed that unilateral blockade of muscarinic receptors simultaneously in both regions in opposite hemispheres, significantly impaired performance. Thus, object-in-place associative memory depends upon cholinergic modulation of neurones within the PRH-PFC circuit.Recognition memory enables individuals to judge whether stimuli have been encountered before. In its most basic form such judgments may be made on the basis of simply whether a stimulus is familiar or novel (familiarity discrimination). However, these judgments may also be made using associations formed between a stimulus and the location or environmental setting in which it was previously encountered. Such object-in-place associative memory in animals is of particular interest as it is acquired rapidly and it requires the integration of object and spatial information and thus has been described as an analog of human episodic memory (Wilson et al. 2008).The perirhinal cortex (PRH) in the medial temporal lobe is a critical neural structure for object recognition and object-in-place associative memory (Bussey et al. 2000; Barker et al. 2007), but unlike object recognition, this memory process is also dependent on the medial prefrontal cortex (mPFC) (Kesner and Ragozzino 2003; Browning et al. 2005; Barker et al. 2007) and crucially it has been shown to depend upon a functional interaction between the PRH and mPFC, with each region making a distinct cognitive contribution to the memory formation (Barker et al. 2007; Barker and Warburton 2008).Having identified two neural regions critical for object-in-place associative memory, we now extend our investigations to explore the underlying cellular mechanisms mediating acquisition or retrieval of this memory process. The present study focused on the neurotransmitter acetylcholine as cholinergic innervation of the PRH is crucial for familiarity discrimination (Tang et al. 1997; Easton and Gaffan 2001; Warburton et al. 2003; Abe et al. 2004; Winters and Bussey 2005). In contrast, the role of muscarinic receptor neurotransmission in the PRH or mPFC in object-in-place associative memory is unknown. Further, while it might appear that object recognition memory and object-in-place memory are likely to share common neural substrates, recent data from our laboratory suggest that this may not be the case (Griffiths et al. 2008).To explore the importance of muscarinic cholinergic neurotransmission within the PRH-mPFC circuit for object-in-place memory, rats were implanted with bilateral cannulae aimed at the PRH or mPFC or both regions to allow direct intracerebral administration of scopolamine during distinct stages of an object-in-place task. Memory performance was tested following either a short (5 min) or long (1 h) retention delay. All animal procedures were performed in accordance with the United Kingdom Animals Scientific Procedures Act (1986) and associated guidelines. Details of the surgery, infusion procedures, behavioral testing, and histology have been published previously (Barker and Warburton 2008). Briefly, male DA rats (230–250 g, Bantin and Kingman, UK) housed under a 12-h/12-h light/dark cycle (light phase 18:00–6:00 h), were anesthetized with isoflurane (induction 4%, maintenance 2%–3%) and surgically implanted with bilateral cannulae aimed at either the PRH or mPFC or both regions. After a two-week recovery period all rats were handled, habituated, and then tested in the object-in-place memory task.Sample phase: Each rat was placed in a black open-topped wooden arena (50 × 90 × 100 cm) containing four different objects (A, B, C, D) constructed from “Duplo” (Lego UK Ltd.). The walls of the arena were surrounded with a black cloth to a height of 1.5 m, and the floor covered with sawdust. The objects were placed 15 cm from the walls (see Fig. 1A) and each rat was allowed to explore the objects for 5 min, after which it was removed for the delay (5 min or 1 h). Exploratory behavior was defined as the animal directing its nose toward the object at a distance of <2 cm. Any other behavior, such as looking around while sitting on or resting against the object, was not recorded. Subjects that failed to complete a minimum of 15-s exploration in the sample phase or 10 s of exploration in the test phase were excluded from the analysis.Open in a separate windowFigure 1.Diagrammatic representations of the individual infusion sites in each animal. (A) Bilateral medial prefrontal (mPFC) group. (B) Bilateral perirhinal (PRH) group. (C) The mPFC infusion sites of the PRH+mPFC group. (D) The PRH infusion sites of the PRH+mPFC group. All of the infusion sites were within the PRH or mPFC.Test phase: Two of the objects, e.g., B and D, exchanged positions and the subjects were replaced in the arena for 3 min. The time spent exploring the two objects that had changed position was compared to the time spent exploring the two objects that had remained in the same position. If object-in-place memory is intact, subjects spend more time exploring the “moved” objects, compared to the “unmoved” objects. Scopolamine hydrobromide (Sigma-Aldrich) dissolved in sterile 0.9% saline solution was administered at a dose of 10 μg/μL per hemisphere (Schroeder and Packard 2002; Warburton et al. 2003; Winters et al. 2006); control infusions consisted of saline. The infusions were given either 15 min before the sample phase or 15 min before the test phase. At the end of the experiment, each rat was anesthetized and perfused transcardially. Coronal brain sections (40 μm) were stained with cresyl-violet to verify the cannulae locations. All the rats in the PRH group had the tip of the bilateral cannulae in the PRH and all the rats in the mPFC group had tips in the ventral portion of the prelimbic or dorsal portion of the infralimbic region of the prefrontal cortex (Fig. 1B). From unpublished observations, using Indian ink and radiolabeled scopolamine, the region infused is estimated to be 1–1.5 mm³, and largely confined to perirhinal cortex or the prelimbic/infralimbic regions of the prefrontal cortex. This spread is consistent with previously quoted results in other brain regions (Martin 1991; Izquierdo et al. 2000; Attwell et al. 2001). Figure 2, A and B show the performance of the rats receiving bilateral infusions of scopolamine or vehicle into either the PRH (n = 12) or mPFC (n = 12) 15 min prior to the sample phase. After a minimum of 48 h, vehicle or scopolamine was infused in a cross-over design and the animal retested using different objects. A three-way ANOVA (drug × region × delay) showed that scopolamine infusion into either region significantly impaired the acquisition of object-in-place memory (main effect of drug F _(1,35) = 63.87, P < 0.001). The magnitude of the deficit was similar irrespective of the region into which scopolamine was infused (region F _(1,35) < 1.0) or the delay employed (delay F _(1,35) < 1.0). Further analyses to examine whether individual groups discriminated between the objects, using a within subjects t-test (two-tailed), confirmed that vehicle-treated animals in the PRH and mPFC groups showed a significant preference for the moved objects over the objects that had remained in the same position, irrespective of the retention delay (PRH 5 min t ₍₉₎ = 2.96, P < 0.02; 1 h t ₍₁₀₎ = 5.71, P < 0.001: mPFC 5 min t ₍₅₎ = 5.47, P < 0.005; 1 h t ₍₁₁₎ = 9.89, P < 0.001), while scopolamine infusion into the PRH or mPFC significantly disrupted the animal''s ability to discriminate (PRH 5min t ₍₉₎ = 0.13, P = 0.9; 1 h t ₍₁₀₎ = 0.92, P = 0.38: mPFC 5 min t ₍₅₎ = 0.051, P = 0.961; 1 h t ₍₁₁₎ = 0.68, P = 0.51). Scopolamine was without effect on the total amount of exploration completed in the sample or test phases (all Fs < 1.0).Open in a separate windowFigure 2.Discrimination between the objects was calculated using a discrimination ratio, which takes into account individual differences in the total amount of exploration. The discrimination ratio is calculated as follows: the difference in time spent by each animal exploring objects that changed position compared to the objects that remained in the same position divided by the total time spent exploring all objects. (A) Infusion of scopolamine (Scop) into the perirhinal cortex (PRH) significantly impaired performance in the object-in-place task following a 5 min and a 1 h delay. (B) Infusion of scopolamine (Scop) into the medial prefrontal cortex (mPFC) significantly impaired performance in the object-in-place task following a 5 min and a 1 h delay. Illustrated for each group is the mean (+ SEM) discrimination ratio. * P < 0.05; ** P < 0.01; and *** P < 0.001 difference between groups.It could be argued that the impairment produced by intracortical infusions of scopolamine following a short delay, reflects an effect on retrieval as well as acquisition. Therefore, we examined the effect of pretest administration of scopolamine (infusion 15 min before the start of the test phase) in the mPFC or PRH following a 1 h delay. No significant impairments were found (mean discrimination ratio ± SEM: PRH vehicle 0.38 ± 0.07, scopolamine 0.46 ± 0.11; mPFC vehicle 0.37 ± 0.08, scopolamine 0.44 ± 0.05), confirmed by a nonsignificant drug effect (F _(1,14) < 1.0, P > 0.1) and nonsignificant drug × area interaction (F _(1,14) = <  1.0, P > 0.1). In addition all groups significantly discriminated between the moved objects compared to objects in the same location (PRH vehicle t ₍₇₎ = 4.95, P < 0.01; PRH scopolamine t ₍₇₎ = 3.45, P < 0.05; mPFC vehicle t ₍₇₎ = 4.26, P < 0.01; mPFC scopolamine t ₍₇₎ = 8.37, P < 0.01). Scopolamine was without effect on the total amount of exploration completed in the test phase (drug × region F _(1,14) < 1.0, P > 0.05).To evaluate the importance of intrahemispheric interactions between these cortical regions and the cholinergic system, a third group of animals had cannulae implanted into both the PRH and mPFC (n = 12). In this experiment the behavioral effects of unilateral scopolamine infusions into the PRH and mPFC in the same hemisphere (Scop Ipsi) were compared with the effects of unilateral scopolamine infusions into opposite hemispheres (Scop Contra). The animals assigned to the Scop Ipsi group on day one, received infusions into opposite hemispheres (Scop Contra) on day two (minimum of 48 h later). Likewise, the animals in the Scop Contra group on day one, received ipsilateral infusions on day two. Figure 3 shows discrimination performance following a 5 min or 1 h delay. A two-way within-subject ANOVA revealed that the Scop Contra group was significantly impaired (infusion F _(1,20) = 44.35, P < 0.001) irrespective of the delay (infusion × delay F _(1,20) < 1.0, P < 0.05). Further analysis confirmed that the Scop Contra group failed to discriminate between the moved and unmoved objects (5 min t ₍₁₀₎ = 0.70, P > 0.1; 1 h t ₍₁₀₎ = 1.03, P > 0.1), while the Scop Ipsi group preferentially explored the moved objects (5 min t ₍₁₀₎ = 9.99, P < 0.0001; 1 h t ₍₁₀₎ = 4.34, P = 0.001).Open in a separate windowFigure 3.Unilateral scopolamine infusions into the PRH and mPFC in opposite hemispheres (Scop Contra) impaired object-in-place performance following both a 5 min and a 1 h delay. Scopolamine infusions into both the PRH and mPFC in the same hemisphere (Scop Ipsi) had no effect on performance following either delay. ** P < 0.01 and *** P < 0.001 difference between groups.Scopolamine was without effect on overall exploration levels during the sample (infusion × delay F _(1,20) < 1.0, P > 0.05; infusion F _(1,20) < 1.0, P > 0.05; delay F _(1,20) < 1.0, P > 0.05) or test phases (infusion × delay F _(1,20) < 1.0, P  >  0.05; infusion F _(1,20)  <  1.0, P > 0.05). There was a significant main effect of delay (F _(1,20) = 10.67, P < 0.01), as the Scop Ipsi and Scop Contra groups completed a greater amount of exploration in the test phase following a 1 h delay compared to a 5 min delay.These results demonstrate that acquisition, but not retrieval of object-in-place memory, is dependent upon muscarinic cholinergic neurotransmission in both the mPFC and PRH. Thus, acute bilateral administration of scopolamine directly into the mPFC or PRH before the sample phase impaired both short- and long-term memory performances. In contrast administration of scopolamine into either the mPFC or PRH prior to the test phase had no effect. Significantly, co-administration of scopolamine into the PRH and mPFC in opposite hemispheres produced a significant impairment in both short-term and long-term object-in-place memory compared to performance following co-administration of scopolamine into the PRH and mPFC in the same hemisphere. Thus, concomitant activation of cholinergic muscarinic receptors is necessary in both regions for the formation of object-in-place associative recognition memory.Our previous studies investigating the role of the mPFC and PRH in object-in-place associative memory suggest that these regions make different cognitive contributions to this mnemonic process. Thus, the PRH appears to be primarily involved in the acquisition of “object” information, while we have hypothesized that the role of the mPFC is to integrate object and place information (Barker et al. 2007). As administration of scopolamine into either region disrupted performance following a long- or short-retention delay, the present data suggest that the neural mechanisms underlying both these different cognitive processes must be dependent upon cholinergic neurotransmission.The results demonstrate that muscarinic receptor neurotransmission is clearly critical for acquisition of the object-in-place task as no impairment was produced when scopolamine was administered only prior to the test phase. While the current study is the first to investigate the importance of cholinergic neurotransmission in object-in-place associative memory, a number of previous studies have shown that intra-PRH infusions of scopolamine block discrimination of novel and familiar objects when administered prior to the sample phase, but not when administered immediately after the sample phase or prior to the test phase (Aigner and Mishkin 1986; Aigner et al. 1991; Warburton et al. 2003; Winters et al. 2006). Thus, together these results support the hypothesis that muscarinic cholinergic neurotransmission within the PRH is necessary for encoding representations of new visual stimuli for subsequent recognition (Turchi et al. 2005), but not for the retrieval of such information. The present results also show for the first time that muscarinic receptor neurotransmission within the mPFC is crucial for the encoding, but not the retrieval of object-in-place memory.It may be argued that the disruptions in performance following administration of scopolamine reflect disruptions in attentional processing. Indeed muscarinic cholinergic neurotransmission in the prefrontal cortex has been implicated in both mnemonic and attentional processes (Voytko et al. 1994; Everitt and Robbins 1997; Chudasama et al. 2004; Dalley et al. 2004). However, deficits in attentional processing are typically observed when the attentional demands of the tasks are high, for example, when very short (millisecond) stimulus exposure times are used (Chudasama et al. 2004; Dalley et al. 2004). In the present study, the exposure time to the stimuli is relatively long (minutes); further there was no evidence of a drug-associated change in explorative behavior following either an infusion into the mPFC or PRH or simultaneously into both regions. Thus, it seems unlikely that the impairments in memory observed can be attributed purely to an attentional deficit, although it is possible that during the encoding of the object-in-place task attentional processes are also recruited involving the cholinergic afferents to the mPFC or PRH.The results showing that simultaneous muscarinic cholinergic blockade in the PRH and mPFC produces a significant impairment in performance support our previous findings of a neural system for object-in-place memory and extend these findings to show that cholinergic neurotransmission is a key component within the system. Our results also support those studies in primates demonstrating a circuit involving the basal forebrain, frontal cortex, and inferior temporal cortex is necessary for object memory encoding (Easton et al. 2002; Easton and Parker 2003).Results from our laboratory have shown that the maintenance of long-term, but not short-term, object-in-place memory is critically dependent upon concurrent NMDA receptor activation in the PRH and mPFC (Barker and Warburton 2008), while short-term object-in-place performance is dependent upon kainate receptor activation in the PRH. Hence, we have argued that there may be multiple cellular mechanisms underlying encoding of information for the short or long term. The present study contrasts with these findings as it demonstrates the necessity for muscarinic receptor activation for both short- and long-term object-in-place memory. Primate studies have indicated that a synergistic interaction between the cholinergic and glutamatergic systems plays an important role in the regulation of visual recognition memory (Matsuoka and Aigner 1996). Hence, further investigations are warranted to explore such interactions in the rat; for example, an interaction between NMDA and muscarinic receptor neurotransmission may mediate long-term recognition memory, while a kainate–muscarinic receptor interaction may mediate short-term recognition memory. Further, the extent to which the contribution of the cholinergic system to encoding of object-in-place memory within the PRH-mPFC system is the same for both short- or long-term memory is unknown.Our results have demonstrated that when a subject is required to use information concerning an association between an object and a place to produce a behavioral response, muscarinic cholinergic receptors in the mPFC are involved. Further, the object-in-place task requires the subject to acquire and remember the topographical relationship between the objects, a process that is known to depend upon the parietal cortex (Goodrich-Hunsaker et al. 2005). The precise contribution of object and spatial information processing in the parietal cortex to the operation of the PRH-mPFC circuit has yet to be determined.In conclusion, the cholinergic projections to the PRH and mPFC originating in the basal forebrain (Wenk et al. 1980) are an important component of the neural mechanisms underlying short- and long-term object-in-place associative memory.     

The role of event relevance and congruence to social groups in flashbulb memory formation

ABSTRACT

Flashbulb memories are vivid, confidently held, long-lasting memories for the personal circumstances of learning about an important event. Importance is determined, in part, by social group membership. Events that are relevant to one’s social group, and furthermore, are congruent with the prior beliefs of that group, should be more likely to be retained as flashbulb memories. The Fukushima nuclear disaster was relevant to ongoing political conversations in both Germany and the Netherlands, but, while the disaster was congruent with German beliefs about the dangers of nuclear energy, it was incongruent with Dutch support for nuclear power. Danish participants would not have found the disaster to be particularly relevant. Partially consistent with this prediction, across two samples (N?=?265 and N?=?518), German participants were most likely to have flashbulb memories for the Fukushima disaster. Furthermore, event features thought to be related to flashbulb memory formation (e.g. ratings of importance and consequentiality) also differed as a function of nationality. Spontaneously generated flashbulb memories for events other than Fukushima also suggested that participants reported events that were relevant to national identity (e.g. the Munich attacks for Germans, the Utøya massacre for Danes, and Malaysian Airlines flight MH-17 for Dutch participants).     

Task-dependent role for dorsal striatum metabotropic glutamate receptors in memory

The effect of post-training intradorsal striatal infusion of metabotropic glutamate receptor (mGluR) drugs on memory consolidation processes in an inhibitory avoidance (IA) task and visible/hidden platform water maze tasks was examined. In the IA task, adult male Long-Evans rats received post-training intracaudate infusions of the broad spectrum mGluR antagonist α-methyl-4-carboxyphenylglycine (MCPG; 1.0, 2.0 mM/0.5 μL), the group I/II mGluR agonist 1-aminocyclopentane-1,3-carboxylic acid (ACPD; 0.5 or 1.0 μM/0.5 μL), or saline immediately following footshock training, and retention was tested 24 h later. In the visible- and hidden-platform water maze tasks, rats received post-training intracaudate infusions of ACPD (1.0 μM), MCPG (2.0 mM), or saline immediately following an eight-trial training session, followed by a retention test 24 h later. In the IA task, post-training infusion of ACPD (0.5 and 1.0 μM) or MCPG (1.0 and 2.0 mM) impaired retention. In the IA and visible-platform water maze tasks, post-training infusion of ACPD (1.0 μM), or MCPG (2.0 mM) impaired retention. In contrast, neither drug affected retention when administered post-training in the hidden-platform task, consistent with the hypothesized role of the dorsal striatum in stimulus-response habit formation. When intradorsal striatal injections were delayed 2 h post-training in the visible-platform water maze task, neither drug affected retention, indicating a time-dependent effect of the immediate post-training injections on memory consolidation. It is hypothesized that MCPG impaired memory via a blockade of postsynaptic dorsal striatal mGluR's, while the impairing effect of ACPD may have been caused by an influence of this agonist on presynaptic “autoreceptor” striatal mGluR populations.     

The effects of cholinergic drugs upon recognition memory in rats

This study measured the effects of the muscarinic blocker, scopolamine, upon object recognition. In order to test object recognition, rats were trained to choose between two distinctive goal boxes, one of which was familiar, and the other was novel. Selection of the unfamiliar goal box was always rewarded (nonmatching-to-sample), and new pairs of start/goal boxes were used on every trial.

In the first experiment it was found that injections of 0.05 mg/kg scopolamine hydrochloride and above produced significant impairments on this nonspatial test of working memory. A second experiment examined whether scopolamine caused a loss of retention by comparing the effects of the drug when the interval between stimulus presentation and choice test was increased from just over 0 sec to 60 sec. While the highest dose of scopolamine hydrobromide (0.06 mg/kg) was sufficient to produce a significant impairment on the longer retention interval, there was no evidence that this dose produced faster forgetting of the stimuli. This result suggests that the drug caused a general depression in performance, which may or may not reflect amnesic properties. In contrast, simultaneous tests with the anticholinesterase, physostigmine, indicated that increasing available acetyl choline might attenuate the effects of the retention intervals. A final series of control tests revealed that the rats relied on cues from a variety of sensory modalities in order to perform the nonmatching task.     

The role of taste and oral somatosensation in olfactory localization

Although there is only one set of olfactory receptors, odours are experienced as smells when sniffing things (e.g., sniffing a wine's bouquet) and as flavours when the olfactory stimulus is present in the mouth (e.g., drinking wine). How this location binding—external versus internal environment—is achieved is poorly understood. Experiment 1 employed a new procedure to study localization, which was then used to explore whether localization is primarily dependent upon simultaneous oral somatosensation. Experiment 2, using solutions of varying viscosity, and Experiment 3, using oral movement of varying vigour, revealed that sniffed odours are not localized to the mouth by somatosensation alone. Instead, Experiment 4 demonstrated that a tastant needs to be present and that increasing tastant concentration generates increasing oral localization. Experiment 5 found that this reliance upon gustation reflects the previously observed “confusion” that people show for taste and smell stimuli in the mouth. We suggest that this “confusion” reflects the gustatory system's superior ability to suppress olfactory attention, thus assisting flavour binding.     

Muscarinic cholinergic influences in memory consolidation

The central cholinergic system and muscarinic cholinergic receptor (mR) activation have long been associated with cognitive function. Although mR activation is no doubt involved in many aspects of cognitive functioning, the extensive evidence that memory is influenced by cholinergic treatments given after training either systemically or intra-cranially clearly indicates that cholinergic activation via mRs is a critical component in modulation of memory consolidation. Furthermore, the evidence indicates that activation of mRs in the basolateral amygdala (BLA) plays an essential role in enabling other neuromodulatory influences on memory consolidation. Memory can also be affected by posttraining activation of mRs in the hippocampus, striatum and cortex. Evidence of increases in hippocampal and cortical acetylcholine (ACh) levels following learning experiences support the view that endogenous ACh release is involved in long-term memory consolidation. Furthermore, the findings indicating that mR drug treatments influence plasticity in the hippocampus and in sensory cortices strongly suggest that mR activation is involved in the storage of information in these brain regions.     

Cognitive processes supporting episodic memory formation in childhood: The role of source memory,binding, and executive functioning

Episodic memories contain various forms of contextual detail (e.g., perceptual, emotional, cognitive details) that need to become integrated. Each of these contextual features can be used to attribute a memory episode to its source, or origin of information. Memory for source information is one critical component in the formation of episodic memories. Likewise, the establishment of episodic memories also requires binding, which reflects the process of encoding the relations among stimuli and provides the experience that certain features of a memory episode belong together. The aims of the present review are to explore the roles of (1) cognitive and neural mechanisms involved in source memory and binding and how the development of these cognitive processes relates to episodic memory formation in childhood and (2) other higher-order cognitive processes, namely executive functioning, in early episodic memory development. We conclude by examining the challenges within this field of research, highlighting the role of other cognitive processes (e.g., sense of self, language, use of strategies) that may contribute to episodic memory formation, addressing areas that can be improved with additional research, and exploring directions for future work.     

The role of representational volatility in recognizing pre- and postchange objects

Theories relating attention to change blindness (CB) imply that representations of objects in the focus of attention are stable and coherent. However, CB occurs for objects in the focus of attention. Here, we explore this apparent contradiction and the possibility that changes can be detected without having a complete and stable representation of the prechange object. The first experiment required observers to recognize a prechange object and a postchange object after viewing arrays of various sizes in which the prechange object was replaced by the postchange object after a brief delay. Results indicated that the representation of the prechange object was strong enough to cue a change but not strong enough to support accurate recognition. The remaining experiments demonstrated that the representation of the prechange object is volatile in that a shift in the display or the presence of a postchange object can disrupt the representation. These findings add to current theories of attention and representations by showing that attention may result in volatile representations that can support change detection without supporting accurate recognition.     

Rho-associated kinase in the gustatory cortex is involved in conditioned taste aversion memory formation but not in memory retrieval or relearning

Rho-associated kinase (ROCK) is intimately involved in cortical neuronal morphogenesis. The present study explores the roles of ROCK in conditioned taste aversion (CTA) memory formation in gustatory cortex (GC) in adult rat. Microinjection of the ROCK inhibitor Y-27632 into the GC 30 min before CTA training or 10 min after the conditioned stimulus (CS) impaired long-term CTA memory (LTM) formation. ROCK inhibitor had no effect on taste aversion when injected before the first LTM test day and did not alter taste aversion on subsequent test days. Microinjection of ROCK inhibitor into GC 30 min before preexposure to the taste CS had no effect on latent inhibition of CTA learning suggesting that ROCK is involved in CS-US association rather than taste learning per se. Cumulatively, these results show that ROCK is needed for normal CTA memory formation but not retrieval, relearning or incidental taste learning.     

The role of the insular cortex in taste function

In spite of over 30 years of research, the role of the Insular Cortex (IC) in taste memory still remains elusive. To study the role of the IC in taste memory, we used conditioned taste aversion (CTA) for two different concentrations of saccharin; 0.1% which is highly preferred, and 0.5% which is non-preferred. Rats that had been IC lesioned bilaterally with ibotenic acid (15 mg/ml) before CTA showed significant learning impairments for saccharin 0.1% but not for saccharin 0.5%. To test CTA memory retention, rats lesioned a week after CTA training became completely amnesic for saccharin 0.1% yet only mildly impaired for saccharin 0.5%. Interestingly, the resulting preference for either concentration matched that of IC lesioned animals when exposed to either saccharin solution for the first time, but not those of sham animals, implying that IC lesions after CTA for either saccharin solution rendered complete amnesia, irrespective of the original preference. Our data indicate that an intact IC is essential for CTA learning and retention, as well as for an early neophobic response, but not for taste preference itself. Our data supports a model where the IC is involved in general taste rejection.