Defensive responses of Wistar and Sprague-Dawley rats to cat odour and TMT

Cat odour and trimethylthiazoline (TMT) are two predator odours commonly used to study defensive behaviour in rats. However their reported efficacy varies markedly across laboratories. We assessed whether rat strain differences might explain such variation. Wistar and Sprague-Dawley rats were tested for unconditioned and conditioned responses to both odours. Cat odour produced robust unconditioned and conditioned defensive behaviour, with notably stronger effects in Wistar rats. TMT produced limited unconditioned avoidance, but failed to elicit conditioned responses in either strain. Results support suggestions that faeces-derived odours such as TMT are less predictive of a predator threat than those derived from fur or skin, and identify the possibility that strain differences affect the defensive response seen to predator odours.     

The hippocampus influences assimilation and accommodation of schemata that are not hippocampus‐dependent

Learning is facilitated when information can be incorporated into an already learned set of rules or ‘mental schema’. The location of a new restaurant, for example, is learned more easily if the neighbourhood's general layout is already known. This type of information is processed by the hippocampus and stored as a schema in the cortex, but it is not known whether the hippocampus can also map new stimuli to cortical schemata that are hippocampus‐independent, such as odour classification. Using a hippocampus‐independent odour‐rule task we found that animals without a functional hippocampus learnt which odours did not fit the rule faster than sham animals, which persistently applied the rule to all odours. Conversely, when non‐fitting odours were linked to a new rule sham animals were faster to link these odours to the new rule. The hippocampus, thus, regulates the association of stimuli with existing schemata even when the schemata are hippocampus‐independent. © 2016 Wiley Periodicals, Inc.     

Reactivity to conditioned threat cues is distinct from exploratory drive in the elevated plus maze

Fear and anxiety are adaptive states that allow humans and animals alike to respond appropriately to threatening cues in their environment. Commonly used tasks for studying behaviour akin to fear and anxiety in rodent models are Pavlovian threat conditioning and the elevated plus maze (EPM), respectively. In threat conditioning the rodents learn to associate an aversive event with a specific stimulus or context. The learnt association between the two stimuli (the ‘memory’) can then be recalled by re-exposing the subject to the conditioned stimulus. The elevated plus maze is argued to measure the agoraphobic avoidance of the brightly lit open maze arms in crepuscular rodents. These two tasks have been used extensively, yet research into whether they interact is scarce. We investigated whether recall of an aversive memory, across contextual, odour or auditory modalities, would potentiate anxiety-like behaviour in the elevated plus maze. The data did not support that memory recall, even over a series of time points, could influence EPM behaviour. Furthermore, there was no correlation between EPM behaviour and conditioned freezing in independent cohorts tested in the EPM before or after auditory threat conditioning. Further analysis found the production of 22 kHz ultrasonic vocalisations revealed the strongest responders to a conditioned threat cue. These results are of particular importance for consideration when using the EPM and threat conditioning to identify individual differences and the possibility to use the tasks in batteries of tests without cross-task interference.     

Electrophysiological responses of rat olfactory tubercle neurons to biologically relevant odours

Biologically relevant odours were used to stimulate olfactory tubercle neurons in anaesthetized male rats. Among 120 recorded neurons, 118 showed spontaneous activity (mean firing rate, 15.0 ± 1.4 spikes/s). Ninety-eight neurons were exposed to at least one of the four following odour sources: an empty vial, or a vial containing food pellets (familiar odour), a sample of oestrous rat faeces (conspecific sexual odour), or a sample of male fox faeces (predator odour). The proportion of neurons responding with a change in activity was significantly linked to the odour applied. Repetition of the stimulation with the same odour elicited the same activity change. Between 50 and 70% of neuronal activity changes were not accompanied by respiration changes. Fifty-six neurons were exposed successively to all four odours, and 38 of them showed an activity change in response to at least one. The response of a neuron to an odour was not affected by its response to the previous one, and no neuron responded in the same manner to all odours. Conversely, no odour elicited a unique response in this population of neurons. However, the proportions of excited, inhibited and insensitive neurons depended significantly on the odour applied, suggesting that the recruitment of olfactory tubercle neurons is directly dependent on the biological significance of the odour.     

Inhibiting cholinergic signalling in the cerebellar interpositus nucleus impairs motor behaviour

The role of neuromodulators in the cerebellum is not well understood. In particular, the behavioural significance of the cholinergic system in the cerebellum is unknown. To investigate the importance of cerebellar cholinergic signalling in behaviour, we infused acetylcholine receptor antagonists, scopolamine and mecamylamine, bilaterally into the rat cerebellum (centred on interpositus nucleus) and observed the motor effects through a battery of behavioural tests. These tests included unrewarded behaviour during open field exploration and a horizontal ladder walking task and reward-based beam walking and pellet reaching tasks. Infusion of a mix of the antagonists did not impair motor learning in the horizontal ladder walking or the reaching task but reduced spontaneous movement during open field exploration, impaired coordination during beam walking and ladder walking, led to fewer reaches in the pellet reaching task, slowed goal-directed reaching behaviour and reduced reward pellet consumption in a free access to food task. Infusion of the muscarinic antagonist scopolamine on its own resulted in deficits in motor performance and a reduction in the number of reward pellets consumed in the free access to food task. By contrast, infusion of the nicotinic antagonist mecamylamine on its own had no significant effect on any task, except beam walking traversal time, which was reduced. Together, these data suggest that acetylcholine in the cerebellar interpositus nucleus is important for the execution and coordination of voluntary movements mainly via muscarinic receptor signalling, especially in relation to reward-related behaviour.     

Food rewards modulate the activity of song neurons in Bengalese finches

Vocal learning, a critical component of speech acquisition, is a rare trait in animals. Songbirds are a well‐established animal model in vocal learning research; male birds acquire novel vocal patterns and have a well‐developed ‘song system’ in the brain. Although this system is unique to songbirds, anatomical and physiological studies have reported similarities between the song system and the thalamo‐cortico‐basal ganglia circuit that is conserved among reptiles, birds, and mammals. Here, we focused on the similarity of the neural response between these two systems while animals were engaging in operant tasks. Neurons in the basal ganglia of vertebrates are activated in response to food rewards and reward predictions in behavioral tasks. A striatal nucleus in the avian song system, Area X, is necessary for vocal learning and is considered specialized for singing. We found that the spiking activity of singing‐related Area X neurons was modulated by food rewards and reward signals in an operant task. As previous studies showed that Area X is not critical for general cognitive tasks, the role of Area X in general learning might be limited and vestigial. However, our results provide a new viewpoint to investigate the independence of the vocal learning system from neural systems involved in other cognitive tasks.     

Exposure to oestrogen prenatally does not interfere with the normal female-typical development of odour preferences

The neural mechanisms controlling mate recognition and heterosexual partner preference are sexually differentiated by perinatal actions of sex steroid hormones. We previously showed that the most important action of oestrogen during prenatal development is to defeminise and, to some extent, masculinise brain and behaviour in mice. Female mice deficient in alpha-foetoprotein (AFP) due to a targeted mutation in the Afp gene (AFP-KO) do not show any female sexual behaviour when paired with an active male because they lack the protective action of AFP against maternal oestrogens. In the present study, we investigated whether odour preferences, another sexually differentiated trait in mice, are also defeminised and/or masculinised in AFP-KO females due to their prenatal exposure to oestrogens. AFP-KO females of two background strains (CD1 and C57Bl/6j) preferred to investigate male over female odours when given the choice between these two odour stimuli in a Y-maze, and thus remained very female-like in this regard. Thus, the absence of lordosis behaviour in these females cannot be explained by a reduced motivation of AFP-KO females to investigate male-derived odours. Furthermore, the presence of a strong male-directed odour preference in AFP-KO females suggests a postnatal contribution of oestrogens to the development of preferences to investigate opposite-sex odours.     

Repetitive and ritualistic behaviour in children with Prader–Willi syndrome and children with autism

Background Recent research has shown that the range of repetitive behaviour seen in individuals with Prader–Willi syndrome (PWS) extends beyond food‐related behaviour. Methods The presence and intensity of repetitive, rigid and routinized behaviour in children with PWS was compared with that seen in children with another neurodevelopmental condition in which repetitive behaviour is common: children with autism. Parents completed the Childhood Routines Inventory (CRI). Results Contrary to our predictions, controlling for developmental level, children with PWS and children with autism showed similar levels of repetitive and ritualistic behaviour overall and on the two CRI factors measuring ‘just right’ and ‘repetitive’ behaviour. Indeed, the majority of the sample of parents of children with PWS endorsed most items on the CRI. However there was some specificity at the level of individual items with parents of children with PWS more frequently endorsing an item on ‘collecting and storing objects’ and parents of children with autism more frequently endorsing ‘lining up objects’, ‘has a strong preference for certain foods’ and ‘seems aware of detail at home’. Conclusions These findings confirm the range of repetitive behaviours that form part of the behavioural phenotype of PWS, including insistence on sameness and ‘just right’ behaviours, and uncover a surprising overlap with those seen in children with autism. Clinical management for children with PWS should include advice and education regarding management of repetitive and rigid behaviour. Future research should investigate whether the repetitive behaviours that form part of the behavioural phenotype of both PWS and autism are associated with a common neuropsychological, neurotransmitter or genetic origin.     

Synchronization in the prefrontal–striatal circuit tracks behavioural choice in a go–no‐go task in rats

Rodent striatum is involved in sensory‐motor transformations and reward‐related learning. Lesion studies suggest dorsolateral striatum, dorsomedial striatum and nucleus accumbens underlie stimulus–response transformations, goal‐directed behaviour and reward expectation, respectively. In addition, prefrontal inputs likely control these functions. Here, we set out to study how reward‐driven behaviour is mediated by the coordinated activity of these structures in the intact brain. We implemented a discrimination task requiring rats to either respond or suppress responding on a lever after the presentation of auditory cues in order to obtain rewards. Single unit activity in the striatal subregions and pre‐limbic cortex was recorded using tetrode arrays. Striatal units showed strong onset responses to auditory cues paired with an opportunity to obtain reward. Cue‐onset responses in both striatum and cortex were significantly modulated by previous errors suggesting a role of these structures in maintaining appropriate motivation or action selection during ongoing behaviour. Furthermore, failure to respond to the reward‐paired tones was associated with higher pre‐trial coherence among striatal subregions and between cortex and striatum suggesting a task‐negative corticostriatal network whose activity may be suppressed to enable processing of reward‐predictive cues. Our findings highlight that coordinated activity in a distributed network including both pre‐limbic cortex and multiple striatal regions underlies reward‐related decisions.     

Lesions of the basal forebrain impair reversal learning but not shifting of attentional set in rats

The cholinergic neurons of the basal forebrain, which project to cortex, the thalamic reticular nucleus and the amygdala, are implicated in many aspects of attentional function, while the intrinsic neurons of the basal forebrain are implicated in learning and memory. This study compared the effects of lesions of the basal forebrain made with either the immunotoxin 192-IgG-saporin (which selectively destroys cholinergic neurons), or the non-selective excitotoxin, ibotenic acid (which destroys both cholinergic and non-cholinergic neurons) on a task which measure the acquisition and shifting of attentional set as well as the ability to learn reversals of specific stimulus-reward pairings. Rats learned to obtain food reward by digging in small bowls containing distinctive digging media that were differentially scented with distinct odours. They performed a series of two-choice discriminations, with the bait associated with either the odour or the digging medium. Rats with 192-IgG-saporin lesions of the basal forebrain were not impaired relative to control rats at any stage of the task. Rats with ibotenic acid lesions of the basal forebrain were impaired the first time stimulus-reward contingencies were reversed. They were not impaired in acquisition of new discriminations, even when an attentional-shift was required. These data are consistent with data from marmosets and so highlight the functional similarity of monkey and rodent basal forebrain. They also confirm the likely involvement of non-cholinergic neurons of the basal forebrain in reversal learning.     

Orexin gene transfer into the amygdala suppresses both spontaneous and emotion‐induced cataplexy in orexin‐knockout mice

Narcolepsy is a chronic sleep disorder linked to the loss of orexin‐producing neurons in the hypothalamus. Cataplexy, a sudden loss of muscle tone during waking, is an important distinguishing symptom of narcolepsy and it is often triggered by strong emotions. The neural circuit underlying cataplexy attacks is not known, but is likely to involve the amygdala, a region implicated in regulating emotions. In mice models of narcolepsy, transfer of the orexin gene into surrogate neurons has been successful in ameliorating narcoleptic symptoms. However, it is not known whether this method also blocks cataplexy triggered by strong emotions. To examine this possibility, the gene encoding mouse prepro‐orexin was transferred into amygdala neurons of orexin‐knockout (KO) mice (rAAV‐orexin; n = 8). Orexin‐KO mice that did not receive gene transfer (no‐rAAV; n = 7) or received only the reporter gene (rAAV‐GFP; n = 7) served as controls. Three weeks later, the animal's sleep and behaviour were recorded at night (no‐odour control night), followed by another recording at night in the presence of predator odour (odour night). Orexin‐KO mice given the orexin gene transfer into surrogate amygdala neurons had significantly less spontaneous bouts of cataplexy, and predator odour did not induce cataplexy compared with control mice. Moreover, the mice with orexin gene transfer were awake more during the odour night. These results demonstrate that orexin gene transfer into amygdala neurons can suppress both spontaneous and emotion‐induced cataplexy attacks in narcoleptic mice. It suggests that manipulating amygdala pathways is a potential strategy for treating cataplexy in narcolepsy.     

Ventral striatal gamma oscillations are highly variable from trial to trial,and are dominated by behavioural state,and only weakly influenced by outcome value

The human and rodent ventral striatal local field potentials show striking oscillations in the gamma band (~ 40–100 Hz), which have been linked to aspects of behaviour such as reward anticipation and delivery, movement initiation, learning from feedback, and decision‐making. These oscillations show a rich temporal organization, whose relationship with behavioural variables is not well understood. Here, we show that, in rats performing a conditioned approach task, low‐gamma and high‐gamma oscillations during an immobile reward anticipation epoch were largely insensitive to outcome value, even though rats distinguished behaviourally between different outcomes, and single units encoded outcome value. Behaviour was highly stereotyped, yet we observed large variability from trial to trial in the occurrence and timing of these oscillations. Furthermore, higher‐order features such as high‐gamma power leading low‐gamma power, and phase‐amplitude coupling to lower‐frequency bands, were only marginally modulated by outcome value. Moreover, these patterns closely resembled those found during off‐task rest periods in which no rewards could be earned. These observations suggest a new interpretation of ventral striatal gamma oscillations as reflecting a default or resting state, with only minor and highly variable modulation by specific task‐related variables.     

The Controllability Hypothesis: Near‐miss effect points to common neurological machinery in posterior parietal cortex for controllable objects and concepts

In this paper, I postulate that the processing of concepts which are deemed controllable is rooted in neurological machinery located in the posterior parietal cortex specialised for the processing of objects which are immediately actionable because they are within reach. This is demonstrated with reference to the near‐miss effect in gambling behaviour, where it is argued that the configurative proximity of the near‐miss outcome to the win outcome creates the impression that the win outcome is ‘almost within reach’ or controllable. The perceived realisability of the desired outcome increases subjective reward probability and the associated expected action value, which impacts decision‐making and behaviour. When extended to substance addiction, this novel hypothesis adds fresh insight into understanding the motivational effects associated with cue exposure and opportunity for drug‐taking. Moreover, by postulating that a perception of control can be generated to minimise unpleasant affective states, it can also reconcile contrasting models of decision‐making and provide a neurological explanation for the efficacy of mindfulness‐based techniques in treating addictions. With reference to the previously hypothesised link between the self and control, these ideas can provide an explanation for the increased subjective value of self‐associated concepts in the ‘endowment effect’, as well as a neurological correlate for the concept of the ‘narrative self’. This paper therefore provides an innovative and unifying perspective for the study and treatment of behavioural and substance addictions as well as contributing to our neurological understanding of philosophical approaches to the self.     

Reward‐seeking and discrimination deficits displayed by hypodopaminergic mice are prevented in mice lacking dopamine D4 receptors

The dopamine D4 receptor (D4R) is predominantly expressed in the prefrontal cortex, a brain area that integrates motor, rewarding, and cognitive information. Because participation of D4Rs in executive learning is largely unknown, we challenged D4R knockout mice (Drd4^?/?) and their wild‐type (WT) littermates, neonatally treated with 6‐hydroxydopamine (6‐OHDA; icv) or vehicle in two operant learning paradigms. A continuous reinforcement task, in which one food‐pellet was delivered after every lever press, showed that 6‐OHDA‐treated mice (hypodopaminergic) WT mice pressed the reinforcing lever at much lower rates than normodopaminergic WT mice. In contrast, Drd4^?/? mice displayed increased lever pressing rates, regardless of their dopamine content. In another study, mice were trained to solve an operant two‐choice task in which a first showing lever was coupled to the delivery of one food pellet only after a second lever emerged. Interval between presentation of both levers was initially 12 s and progressively shortened to 6, 2, and finally 0.5 s. Normodopaminergic WT mice obtained a pellet reward in more than 75% of the trials at 12, 6, and 2 s, whereas hypodopaminergic WT mice were severely impaired to select the reward‐paired lever. Absence of D4Rs was not detrimental in this task. Moreover, hypodopaminergic Drd4^?/? mice were as efficient as their normodopaminergic Drd4^?/? siblings in selecting the reward‐paired lever. In summary, hypodopaminergic mice exhibit severe impairments to retrieve rewards in two operant positive reinforcement tasks, but these deleterious effects are totally prevented in the absence of functional D4Rs. Synapse 63:991–997, 2009. © 2009 Wiley‐Liss, Inc.     

Abnormal motor cortex excitability during linguistic tasks in adductor‐type spasmodic dysphonia

In healthy subjects (HS), transcranial magnetic stimulation (TMS) applied during ‘linguistic’ tasks discloses excitability changes in the dominant hemisphere primary motor cortex (M1). We investigated ‘linguistic’ task‐related cortical excitability modulation in patients with adductor‐type spasmodic dysphonia (ASD), a speech‐related focal dystonia. We studied 10 ASD patients and 10 HS. Speech examination included voice cepstral analysis. We investigated the dominant/non‐dominant M1 excitability at baseline, during ‘linguistic’ (reading aloud/silent reading/producing simple phonation) and ‘non‐linguistic’ tasks (looking at non‐letter strings/producing oral movements). Motor evoked potentials (MEPs) were recorded from the contralateral hand muscles. We measured the cortical silent period (CSP) length and tested MEPs in HS and patients performing the ‘linguistic’ tasks with different voice intensities. We also examined MEPs in HS and ASD during hand‐related ‘action‐verb’ observation. Patients were studied under and not‐under botulinum neurotoxin‐type A (BoNT‐A). In HS, TMS over the dominant M1 elicited larger MEPs during ‘reading aloud’ than during the other ‘linguistic’/‘non‐linguistic’ tasks. Conversely, in ASD, TMS over the dominant M1 elicited increased‐amplitude MEPs during ‘reading aloud’ and ‘syllabic phonation’ tasks. CSP length was shorter in ASD than in HS and remained unchanged in both groups performing ‘linguistic’/‘non‐linguistic’ tasks. In HS and ASD, ‘linguistic’ task‐related excitability changes were present regardless of the different voice intensities. During hand‐related ‘action‐verb’ observation, MEPs decreased in HS, whereas in ASD they increased. In ASD, BoNT‐A improved speech, as demonstrated by cepstral analysis and restored the TMS abnormalities. ASD reflects dominant hemisphere excitability changes related to ‘linguistic’ tasks; BoNT‐A returns these excitability changes to normal.     

Use of the Interact Short Form as a tool to evaluate emotion of people with profound intellectual disabilities

Background One of the essential purposes of intervention programmes for people with profound intellectual disabilities (ID) is to enhance the desirable mood and behaviour and decrease the undesirable ones through stabilizing their emotion. There is lack of validated instrument to offer a comprehensive measure that covers the mood and behaviour, both desirable and undesirable, appropriate for people with profound ID. Method This study aimed to examine the validity and reliability of the Interact Short Form for evaluating the mood and behaviour of people with profound ID, and at the same time, review their emotional profile using the Interact Short Form. Both content validity using expert panel review and construct validity by means of factor analysis were investigated. A total of 75 people with profound ID were recruited. Inter‐rater reliability was tested. The results of the Interact Short Form were described to reflect the emotional profile of this group of participants. Results Using the results of expert panel review and those from factor analysis, we found three subscales representing the mood and behaviour of people with profound ID. They were: ‘emotional expression’, ‘interests towards tasks’ and ‘behaviours to environment’. All three subscales were found to be internally consistent (α = 0.71–0.88). The Interact Short Form– People with profound ID version also showed good inter‐rater reliability (mean = 0.72). The results of the Interact Short Form showed that this group of participants had fairly stable emotion under the structured setting and activities in the residential institutions where data were collected. Conclusions The Interact Short Form– People with profound ID version serves as a helpful tool for both clinical and research use in assessing the mood and behaviour of people with profound ID in a simple, comprehensive and systematic way.     

Animal neuropsychology: validation of the Intra-Dimensional Extra-Dimensional set shifting task for mice

Research in animal neuropsychology is providing an exciting new generation of behavioral tests for mice that promise to overcome many of the limitations of current high-throughput testing, and provide direct animal homologues of clinically important measures in human research. Set shifting tasks are some of the best understood and widely used human neuropsychological tasks, with clinical relevance to traumatic brain injury, schizophrenia, autism, obsessive compulsive disorder, trichotillomania, and many other disorders. Here we report the first successful modification of a human set shifting neuropsychological task, the Intra-Dimensional Extra-Dimensional (IDED) task, for use with mice. We presented mice with a series of compound discrimination and reversal tasks where one stimulus dimension consistently cued reward. Task performance improved with a new set of compound stimuli, as did reversal performance--indicating the formation of a cognitive-attentional set. We then overtrained a subset of the mice, and presented control and overtrained mice with a new compound discrimination where a novel stimulus dimension cued reward. As is the case in human control subjects, control mice persisted in responding to the now-incorrect stimulus dimension, performing poorly on this extra-dimensional shift compared with the previous intra-dimensional shift, thereby validating the task as a measure of set shifting. Furthermore, overtrained mice were impaired on this extra-dimensional shift compared with controls, further validating the task. The advantages and disadvantages of the IDED task compared to high-throughput approaches are discussed.     

The vomeronasal organ is required for the expression of lordosis behaviour, but not sex discrimination in female mice

The role of the vomeronasal organ (VNO) in mediating neuroendocrine responses in female mice is well known; however, whether the VNO is equally important for sex discrimination is more controversial as evidence exists for a role of the main olfactory system in mate recognition. Therefore, we studied the effect of VNO removal (VNOx) on the ability of female mice to discriminate between volatile and non-volatile odours of conspecifics of the two sexes and in different endocrine states using Y-maze tests. VNOx female mice were able to reliably distinguish between male and female or male and gonadectomized (gdx) male volatile odours. However, when subjects had to discriminate between male and female or gdx male non-volatile odours, VNOx females were no longer able to discriminate between sex or different endocrine status. These results thus show that the VNO is primarily involved in the detection and processing of non-volatile odours, and that female mice can use volatile odours detected and processed by the main olfactory system for mate recognition. However, VNO inputs are needed to promote contact with the male, including facilitation of lordosis responses to his mounts. A single subcutaneous injection with gonadotropin-releasing hormone (GnRH) partially reversed the deficit in lordosis behaviour observed in VNOx females suggesting that VNO inputs may reach hypothalamic GnRH neurons to influence the display of sexual behaviour.     

Evaluation of the APP23-model for Alzheimer's disease in the odour paired-associate test for hippocampus-dependent memory

The APP23 model is a transgenic mouse model for Alzheimer's disease. Cognitive performance in the APP23-model was assessed by Morris Water Maze (MWM) and passive avoidance learning, but the latter failed to show any difference between the genotypes. In search of a non-spatial alternative for assessment of hippocampus-dependent memory, we evaluated an odour paired-associate test, which is based on learning an association between two sets of odours. The protocol includes a shaping phase, in which the animals learn to dig up a reward, a preliminary training phase and a training phase, where the actual association is learned. Subsequently, mice are tested for transitive inference and subjected to a symmetry test. Impairment was seen in the APP23 mice, in comparison with wild type mice, in training; however, both groups failed the transitivity and symmetry test. Possible explanations for this discrepancy with earlier published results are the advanced age of the mice or the C57Bl/6J background, in which the model was established.     

Deficits in hippocampal‐dependent transfer generalization learning accompany synaptic dysfunction in a mouse model of amyloidosis

Elevated β‐amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer's disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the “transfer” of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative “transfer learning” task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APP_swePS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle β‐amyloid‐induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg‐SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal‐dependent learning may be useful for early identification of AD‐like pathology. © 2015 Wiley Periodicals, Inc.