Locus Coeruleus Activation Facilitates Memory Encoding and Induces Hippocampal LTD that Depends on β-Adrenergic Receptor Activation

Spatial memory formation is enabled through synaptic information processing, in the form of persistent strengthening and weakening of synapses, within the hippocampus. It is, however, unclear how relevant spatial information is selected for encoding, in preference to less pertinent information. As the noradrenergic locus coeruleus (LC) becomes active in response to novel experiences, we hypothesized that the LC may provide the saliency signal required to promote hippocampal encoding of relevant information through changes in synaptic strength. Test pulse stimulation evoked stable basal synaptic transmission at Schaffer collateral (SC)–CA1 stratum radiatum synapses in freely behaving adult rats. Coupling of these test pulses with electrical stimulation of the LC induced long-term depression (LTD) at SC–CA1 synapses and induced a transient suppression of theta-frequency oscillations. Effects were N-methyl-D-aspartate and β-adrenergic receptor dependent. Activation of the LC also increased CA1 noradrenalin levels and facilitated the encoding of spatial memory for a single episode via a β-adrenoceptor–dependent mechanism. Our results demonstrate that the LC plays a key role in the induction of hippocampal LTD and in promoting the encoding of spatial information. This LC–hippocampal interaction may reflect a means by which salient information is distinguished for subsequent synaptic processing

Chimpanzees (Pan troglodytes) Fail a What-Where-When Task but Find Rewards by Using a Location-Based Association Strategy

Recollecting the what-where-when of an episode, or episodic-like memory, has been established in corvids and rodents. In humans, a linkage between remembering the past and imagining the future has been recognised. While chimpanzees can plan for the future, their episodic-like memory has hardly been investigated. We tested chimpanzees (Pan troglodytes) with an adapted food-caching paradigm. They observed the baiting of two locations amongst four and chose one after a given delay (15 min, 1 h or 5 h). We used two combinations of food types, a preferred and a less preferred food that disappeared at different rates. The subjects had to base their choices on the time elapsed since baiting, and on their memory of which food was where. They could recover either their preferred food or the one that remained present. All animals failed to obtain the preferred or present foods above chance levels. They were like-wise unsuccessful at choosing baited cups above chance levels. The subjects, thus, failed to use any feature of the baiting events to guide their choices. Nonetheless, their choices were not random, but the result of a developed location-based association strategy. Choices in the second half of the study correlated with the rewards obtained at each location in the first half of the study, independent from the choices made for each location in the first half of the study. This simple location-based strategy yielded a fair amount of food. The animals' failure to remember the what-where-when in the presented set-up may be due to the complexity of the task, rather than an inability to form episodic-like memories, as they even failed to remember what was where after 15 minutes

Enhanced Fear Expression in a Psychopathological Mouse Model of Trait Anxiety: Pharmacological Interventions

The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB), or normal (NAB) anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α2,3,5-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i) for identifying biological factors underlying misguided conditioned fear responses and (ii) for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias

Neurokinin3 receptor antagonism attenuates cocaine's behavioural activating effects yet potentiates its dopamine-enhancing action in the nucleus accumbens core

Several lines of evidence indicate a role for neurokinin3 receptors (NK3-Rs) in behavioural activation and mechanisms governing reinforcement processes. In this study we investigated the effect of pretreatment with the NK3-R antagonist, SR142801, (0.2 and 2.0 mg/kg) on the cocaine-induced (10.0 mg/kg i.p.) increase in extracellular dopaminergic activity in the nucleus accumbens (NAc). In vivo microdialysis in the NAc of freely moving rats showed that cocaine increased concentrations of dopamine (DA) to approximately 350% in the core and approximately 450% in the shell. Pre-treatment with SR142801 significantly potentiated this effect in the core (to approximately 550%), whereas this effect was not found in the shell. We also investigated the effects of NK3-Rs antagonism on cocaine-induced hyperactivity and conditioned place preference. SR142801 blocked the hyperactivity, but neither the conditioned place preference nor the conditioned locomotor activity induced by cocaine, although there was a slight tendency towards a reduced place preference. When given alone, SR142801 had no effects on behaviour or extracellular dopamine concentrations in any of the structures investigated. These data provide evidence for a contribution of NK3-Rs in the acute behavioural and neurochemical effects of cocaine, involving dopaminergic activity in the core of the nucleus accumbens

Neurokinin receptor antagonism attenuates cocaine's behavioural activating effects yet potentiates its dopamine-enhancing action in the nucleus accumbens core.

Several lines of evidence indicate a role for neurokinin3 receptors (NK3-Rs) in behavioural activation and mechanisms governing reinforcement processes. In this study we investigated the effect of pretreatment with the NK3-R antagonist, SR142801, (0.2 and 2.0 mg/kg) on the cocaine-induced (10.0 mg/kg i.p.) increase in extracellular dopaminergic activity in the nucleus accumbens (NAc). In vivo microdialysis in the NAc of freely moving rats showed that cocaine increased concentrations of dopamine (DA) to approximately 350% in the core and approximately 450% in the shell. Pre-treatment with SR142801 significantly potentiated this effect in the core (to approximately 550%), whereas this effect was not found in the shell. We also investigated the effects of NK3-Rs antagonism on cocaine-induced hyperactivity and conditioned place preference. SR142801 blocked the hyperactivity, but neither the conditioned place preference nor the conditioned locomotor activity induced by cocaine, although there was a slight tendency towards a reduced place preference. When given alone, SR142801 had no effects on behaviour or extracellular dopamine concentrations in any of the structures investigated. These data provide evidence for a contribution of NK3-Rs in the acute behavioural and neurochemical effects of cocaine, involving dopaminergic activity in the core of the nucleus accumbens

Lateral entorhinal cortex is necessary for associative but not nonassociative recognition memory

This work was supported by BBSRC [Grant number BB/I019367/1]The lateral entorhinal cortex (LEC) provides one of the two major input pathways to the hippocampus and has been suggested to process the nonspatial contextual details of episodic memory. Combined with spatial information from the medial entorhinal cortex it is hypothesised that this contextual information is used to form an integrated spatially selective, context-specific response in the hippocampus that underlies episodic memory. Recently, we reported that the LEC is required for recognition of objects that have been experienced in a specific context (Wilson et al. (2013) Hippocampus 23:352-366). Here, we sought to extend this work to assess the role of the LEC in recognition of all associative combinations of objects, places and contexts within an episode. Unlike controls, rats with excitotoxic lesions of the LEC showed no evidence of recognizing familiar combinations of object in place, place in context, or object in place and context. However, LEC lesioned rats showed normal recognition of objects and places independently from each other (nonassociative recognition). Together with our previous findings, these data suggest that the LEC is critical for associative recognition memory and may bind together information relating to objects, places, and contexts needed for episodic memory formation.Publisher PDFPeer reviewe