[The effect of a caudal hippocampus lesion on learning in a Morris water maze in bank voles (Clethrionomys glareolus)].

A bilateral cytotoxic lesion of the caudal hippocampus (about 1/3 of the whole hippocampus, which is insufficiently studied) influences learning of bank voles (Clethrionomys glareolus) in the Morris water maze. This effect has been estimated in this paper. A version of the test intended to measure long-term spatial memory was used. The lesion was shown to exert an influence on the learning dynamics by slowing it down, as well as to reduce the accuracy of platform location memorizing at early stages of training. The data obtained indicate the involvement of this area in control of spatial learning in rodents.

Restoration of spatial working memory by genetic rescue of GluR-A-deficient mice.

Gene-targeted mice lacking the AMPA receptor subunit GluR-A (also called GluR1 encoded by the gene Gria1,) have deficits in hippocampal CA3-CA1 long-term potentiation (LTP) and have profoundly impaired hippocampus-dependent spatial working memory (SWM) tasks, although their spatial reference memory remains normal. Here we show that forebrain-localized expression of GFP-tagged GluR-A subunits in GluR-A-deficient mice rescues SWM, paralleling its rescue of CA3-CA1 LTP. This provides powerful new evidence linking hippocampal GluR-A-dependent synaptic plasticity to rapid, flexible memory processing.

Age-dependent and -independent behavioral deficits in Tg2576 mice.

The Tg2576 mouse model of excessive cerebral beta-amyloid deposition is now more than a decade old, yet consensus as to its exact characteristics and utility as a model of Alzheimer's disease is still lacking. Four different cohorts of control and Tg2576 mice, aged approximately 3, 9, 13 and 21 months, were therefore subjected to a battery of tests, principally to assess cognitive and species-typical behaviors. A novel test, the paddling Y-maze, demonstrated an age-dependent deficit in 10 and 14, but not 3 month Tg2576 mice, also in aged (21 month) control mice. However, in many other cognitive tests few Tg2576-related deficits could be shown. This frequently seemed attributable to poor performance of control mice. Tests of species-typical behaviors showed that Tg2576 mice had a deficit in burrowing behavior at all ages. An age-independent deficit was also seen in nest construction, but only when mice were group-housed; most individually housed mice in either group made reasonable nests. Overall, the results suggested that these Tg2576 mice are not a simple, suitable or reliable model for routine screening of treatments for Alzheimer's disease. However, this model might perform better behaviorally on a different genetic background.

Spatial memory dissociations in mice lacking GluR1.

Gene-targeted mice lacking the AMPA receptor subunit GluR1 (GluR-A) have deficits in hippocampal CA3-CA1 long-term potentiation. We now report that they showed normal spatial reference learning and memory, both on the hidden platform watermaze task and on an appetitively motivated Y-maze task. In contrast, they showed a specific spatial working memory impairment during tests of non-matching to place on both the Y-maze and an elevated T-maze. In addition, successful watermaze and Y-maze reference memory performance depended on hippocampal function in both wild-type and mutant mice; bilateral hippocampal lesions profoundly impaired performance on both tasks, to a similar extent in both groups. These results suggest that different forms of hippocampus-dependent spatial memory involve different aspects of neural processing within the hippocampus.

Deletion of glutamate receptor-A (GluR-A) AMPA receptor subunits impairs one-trial spatial memory.

Genetically modified mice lacking the glutamate receptor A (GluR-A) subunit of the AMPA receptor (GluR-A-/- mice) display normal spatial reference memory but impaired spatial working memory (SWM). This study tested whether the SWM impairment in these mice could be explained by a greater sensitivity to within-session proactive interference. The SWM performance of GluR-A-/- and wild-type mice was assessed during nonmatching-to-place testing under conditions in which potential proactive interference from previous trials was reduced or eliminated. SWM was impaired in GluR-A-/- mice, both during testing with pseudotrial-unique arm presentations on the radial maze and when conducting each trial on a different 3-arm maze, each in a novel testing room. Experimentally naive GluR-A-/- mice also exhibited chance performance during a single trial of spontaneous alternation. This 1-trial spatial memory deficit was present irrespective of the delay between the sample information and the response choice (0 or 45 min) and the length of the sample phase (0.5 or 5 min). These results imply that the SWM deficit in GluR-A-/- mice is not due to increased susceptibility to proactive interference.

A comparison of the behavior of C57BL/6 and C57BL/10 mice.

Selection of an appropriate animal model is a crucial first step in many research programs. The C57BL/6 (B6) mouse is the most widely used inbred mouse strain in biomedical research; this is particularly so in behavioral studies. However, there are several C57BL substrains, all derived from common ancestors. C57BL/10 (B10) mice are superficially almost identical to B6 mice in appearance and behavior and widely used in inflammation and immunology research, yet rarely in behavioral studies. The present study assessed the comparability of behavioral results from these two strains, to determine whether they could be used interchangeably in future behavioral experiments. The results showed that the behavior of B6 mice clearly differed from that of B10 mice: in tests of cognition, species-typical behaviors, and motor coordination the B6 strain performed better. Consequently, B6 mice will probably remain the preferred choice for behavioral studies. Interpretation of results derived from the B10 strain should take into account its particular behavioral characteristics.

Retracted: Nrf2: a novel therapeutic target in fragile X syndrome is modulated by NNZ2566.

Retraction: "Nrf2: a novel therapeutic target in fragile X syndrome is modulated by NNZ2566" by R. M. J. Deacon, M. J. Hurley, C. M. Rebolledo, M. Snape, F. J. Altimiras, L. Farías, M. Pino, R. Biekofsky, L. Glass and P. Cogram. The above article, from Genes, Brain and Behavior, published online on 12th May 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Andrew Holmes and John Wiley & Sons Ltd. The retraction has been agreed as all authors cannot agree on a revised author order, and at least one author continues to dispute the original order. In this case, the original article is being retracted on the grounds that the journal does not have permission to publish. Reference: Deacon, R. M. J., Hurley, M. J., Rebolledo, C. M., Snape, M., Altimiras, F. J., Farías, L., Pino, M., Biekofsky, R., Glass, L. and Cogram, P. (2017), Nrf2: a novel therapeutic target in fragile X syndrome is modulated by NNZ2566. Genes, Brain and Behavior. doi:10.1111/gbb.12373.

Behavioral phenotyping of mice lacking the K ATP channel subunit Kir6.2.

ATP-sensitive potassium (K(ATP)) channels are expressed in various tissues and cell-types where they act as so-called metabolic sensors that couple metabolic state to cellular excitability. The pore of most K(ATP) channel types is built by Kir6.2 subunits. Analysis of a general Kir6.2 knockout (KO) mouse has identified a variety of different functional roles for central and peripheral K(ATP) channels in situations of metabolic demand. However, the widespread distribution of these channels suggests that they might influence cellular physiology and animal behavior under metabolic control conditions. As a comprehensive behavioral description of Kir6.2 KO mice under physiological control conditions has not yet been carried out, we subjected Kir6.2 KO and corresponding wild-type (WT) mice to a test battery to assess emotional behavior, motor activity and coordination, species-typical behaviors and cognition. The results indicated that in these test situations Kir6.2 KO mice were less active, had impaired motor coordination, and appeared to differ from controls in their emotional reactivity. Differences between KO and WT mice were generally attenuated in test situations that resembled the home cage environment. Moreover, in their home cages KO mice were more active than WT mice. Thus, our results suggest that loss of Kir6.2-containing K(ATP) channels does affect animal behavior under metabolic control conditions, especially in novel situations. These findings assign novel functional roles to K(ATP) channels beyond those previously described. However, according to the widespread expression of K(ATP) channels, these effects are complex, being dependent on details of test apparatus, procedure and prior experience.

GluR-A-dependent synaptic plasticity is required for the temporal encoding of nonspatial information.

Four related experiments studied operant performance of mice on differential reinforcement of low rates of responding (DRL) paradigms. Experiment 1 showed that excitotoxic hippocampal lesions impaired performance of a 10-s DRL schedule (DRL-10). Experiments 2 and 3 showed that GluR-A AMPA receptor subunit knockout mice, which are deficient in CA3-CA1 long-term potentiation (LTP), were markedly impaired at 15 s (DRL-15), but less impaired at DRL-10. Experiment 4 compared DRL-15 performance in mice from the 2 strains from which the GluR-A colony was derived and showed that they did not differ. The results show that GluR-A-containing AMPA receptors are required for normal performance on hippocampus-dependent, nonspatial working memory tasks, consistent with a role for GluR-A in the temporal encoding (what happened when) of nonspatial information.

Regional dissociations within the hippocampus--memory and anxiety.

The amnestic effects of hippocampal lesions are well documented, leading to numerous memory-based theories of hippocampal function. It is debatable, however, whether any one of these theories can satisfactorily account for all the consequences of hippocampal damage: Hippocampal lesions also result in behavioural disinhibition and reduced anxiety. A growing number of studies now suggest that these diverse behavioural effects may be associated with different hippocampal subregions. There is evidence for at least two distinct functional domains, although recent neuroanatomical studies suggest this may be an underestimate. Selective lesion studies show that the hippocampus is functionally subdivided along the septotemporal axis into dorsal and ventral regions, each associated with a distinct set of behaviours. Dorsal hippocampus has a preferential role in certain forms of learning and memory, notably spatial learning, but ventral hippocampus may have a preferential role in brain processes associated with anxiety-related behaviours. The latter's role in emotional processing is also distinct from that of the amygdala, which is associated specifically with fear. Gray and McNaughton's theory can in principle incorporate these apparently distinct hippocampal functions, and provides a plausible unitary account for the multiple facets of hippocampal function.

GluR-A-Deficient mice display normal acquisition of a hippocampus-dependent spatial reference memory task but are impaired during spatial reversal.

Acquisition and reversal of a spatial discrimination were assessed in an appetitive, elevated plus-maze task in 4 groups of mice: knockout mice lacking the AMPA receptor subunit GluR-A (GluR1), wild-type controls, mice with cytotoxic hippocampal lesions, and controls that had undergone sham surgery. In agreement with previous studies using tasks such as the water maze, GluR-A(-/-) mice were unimpaired during acquisition of the spatial discrimination task, whereas performance in the hippocampalgroup remained at chance levels. In contrast to their performance during acquisition, the GluR-A(-/-) mice displayed a mild deficit during reversal of the spatial discrimination and were profoundly impaired during discrete trial, rewarded-alternation testing on the elevated T maze. The latter result suggests a short-term, flexible spatial working memory impairment in GluR-A(-/-) mice, which might also underlie their mild deficit during spatial reversal.

Medial septal lesions mimic effects of both selective dorsal and ventral hippocampal lesions.

Electrolytic medial septal (MS) lesions, which depleted acetylcholinesterase staining in both dorsal and ventral hippocampus, produced a constellation of behaviors, combining aspects of both selective dorsal and ventral hippocampal lesion effects. MS lesions impaired spatial working memory on the T maze, thus resembling the effects of dorsal hippocampal lesions. In addition, MS lesions reduced anxiety during successive alleys (a modified form of the elevated plus-maze), social interaction, and hyponeophagia tests. MS lesions also reduced postshock freezing. These effects more closely resemble those of ventral hippocampal lesions. Therefore, the effects of electrolytic MS lesions derive from the resulting combined deafferentation of dorsal and ventral hippocampal regions, suggesting that previously reported effects of cytotoxic dorsal hippocampal lesions are unlikely to be due to a demyelination of fibers of passage coursing through the septal pole.

Amygdala and ventral hippocampus contribute differentially to mechanisms of fear and anxiety.

Cytotoxic ventral hippocampal lesions produced anxiolytic effects on 4 ethologically based, unconditioned tests of anxiety in the rat (hyponeophagia, black/white 2-compartment box test, a successive alleys test that represents a modified version of the elevated plus-maze, and a social interaction test). Dorsal hippocampal lesions did not produce anxiolytic effects on these tests, suggesting a distinct specialization of function within the hippocampus. Furthermore, the effects of ventral hippocampal lesions were also distinct from those of amygdala lesions. This suggests that the effects of ventral hippocampal lesions are not simply due to direct or indirect effects on the amygdala, and that these 2 brain areas contribute differentially to a brain system (or systems) associated with the processing of fearful and/or anxiogenic stimuli.

Double dissociation of function within the hippocampus: spatial memory and hyponeophagia.

Complete and dorsal hippocampal lesions impaired spatial performance on 2 working memory tasks: rewarded alternation on the T maze and matching to position in the water maze. In contrast, ventral hippocampal lesions had no effect on these tasks, even when task difficulty was increased by the introduction of delays. Ventral lesions did resemble complete lesions in reducing anxiety in 3 commonly used tests of anxiety (social interaction, plus-maze, and hyponeophagia). Dorsal lesions also appeared to be anxiolytic in the social interaction and plus-maze tests, but they did not affect hyponeophagia. Complete- and dorsal-lesioned rats displayed hyperactivity, whereas ventral-lesioned rats did not. These results show a double dissociation between dorsal and ventral hippocampal lesions (hyponeophagia vs. spatial memory), suggesting differentiation of function along the septotemporal axis of this structure.

A comparison of GluR-A-deficient and wild-type mice on a test battery assessing sensorimotor, affective, and cognitive behaviors.

Previous studies have demonstrated a spatial working memory deficit in glutamate receptor (GluR)-A (GluR1) AMPA receptor subunit knockout mice. The present study evaluated male and female wild-type and GluR-A-/- mice on a test battery that assessed sensorimotor, affective, and cognitive behaviors. Results revealed a behavioral phenotype more extensive than previously described. GluR-A-/- mice were hyperactive, displayed a subtle lack of motor coordination, and were generally more anxious than wild-type controls. In addition, they showed a deficit in spontaneous alternation, consistent with previous reports of a role for GluR-A-dependent plasticity in hippocampus-dependent, spatial working memory. Although changes in motor coordination or anxiety cannot explain the dissociations already reported within the spatial memory domain, it is clear that they could significantly affect interpretation of results obtained in other kinds of behavioral tasks.

Ventral hippocampal lesions affect anxiety but not spatial learning.

Rats with cytotoxic ventral hippocampal lesions which removed approximately 50% of the hippocampus (including dentate gyrus) starting from the temporal pole, displayed a reduction in freezing behaviour following the delivery of an unsignalled footshock in an operant chamber. This was more plausibly a result of reduced susceptibility to fear than a result of a lesion-induced increase in general motor activity. There was no consistent difference between sham and lesioned animals in spontaneous locomotor activity, or locomotion following acute or chronic treatment with amphetamine. In contrast, ventral hippocampal lesioned animals were quicker to pass from the black to the white box during a modified version of the light/dark exploration test, and were quicker to begin eating during tests of hyponeophagia. Furthermore, rats with ventral hippocampal lesions defecated less than their sham counterparts both during open field testing and in extinction sessions following contextual conditioning. In contrast to these clear lesion effects, there were no signs of any spatial learning impairment either in the watermaze or on the elevated T-maze. Taken together these results suggest that the ventral hippocampus may play a role in a brain system (or systems) associated with fear and/or anxiety, and provide further evidence for a distinct specialisation of function along the septotemporal axis of the hippocampus.

Naked mole-rats: behavioural phenotyping and comparison with C57BL/6 mice.

Naked mole-rats (NMR) live underground in large eusocial colonies in East Africa. They are extremely long-lived, some individuals having a lifespan of over 30 years. This has attracted research into longevity and possibly neurodegenerative disorders. However, very little is known about their basic behaviour, particularly in tests commonly used to characterise the behaviour of the laboratory rat and mouse, for which there is an enormous database. Recently the authors carried out comprehensive behavioural phenotyping on NMRs, comparing them on most tasks directly with C57BL/6 mice, the strain for which there is the largest behavioural database. The NMR colony had been obtained from the wild originally, but housed in an animal facility for about two years. Large inter-species differences in behaviour were seen between the mice and the NMRs. The latter had generally poor sensorimotor function, including cutaneous sensation, strength and even grasp reflexes. They were often reluctant to enter or head-dip into small holes that mice readily entered. Their vision (generally considered to be very poor) was sufficient to distinguish the two zones of a light-dark box. Although, as expected, the NMRs were capable of burrowing and digging, when individually housed they did not shred cotton material to make nests. Shredding was seen in a colony cage containing a queen, but no nests were made there even when a nesting box was provided. In cognitive testing, although, unlike mice and rats, they did not spontaneously alternate in a T-maze, they learnt rewarded alternation and a cued position task well. This study demonstrates how behaviour uniquely reflects the natural environment in which these unusual animals have evolved and live, and provides baseline data for future work.

Burrowing: a sensitive behavioural assay, tested in five species of laboratory rodents.

In the burrowing test, mice or rats spontaneously empty a tube filled with food pellets, gravel or other substances. The test is extremely simple to perform, the apparatus is inexpensive and readily constructed. It exploits a natural rodent behaviour, provides quantitative data under controlled laboratory conditions, and has proved extremely sensitive to prion disease in mice (Mus musculus), cytokines in rats (Rattus norvegicus), lipopolysaccharide in mice and rats, strain differences and brain lesions in mice. However, it has not been used in other, less common, laboratory species, and might, e.g. be useful in detecting scrapie infection in hamsters (Mesocricetus auratus), a commonly used species in prion disease research. Therefore, the present study systematically investigated burrowing behaviour in five rodent species, using five different burrowing substrates. It also enquired whether rats are unique among rodents in showing little burrowing of food pellets, yet burrow gravel and other earth-like substrates vigorously. The results showed that all the species (rats, mice, hamsters and gerbils (Meriones unguiculatus)), except one (Egyptian spiny mice, Acomys cahirinus, which does not dig burrows in the wild) burrowed earth-like substrates well. However, laboratory mice were the only species that burrowed food pellets vigorously, without prior exposure to other substrates. These results show that burrowing, with an appropriate substrate, can be used as a simple behavioural test in many rodent species. It is an excellent detector of neurobehavioural toxicity with applications in many areas of research, especially when long-term behavioural monitoring is required, e.g. to track changes in chronic disease models.

Aged Tg2576 mice are impaired on social memory and open field habituation tests.

In a previous publication [Deacon RMJ, Cholerton LL, Talbot K, Nair-Roberts RG, Sanderson DJ, Romberg C, et al. Age-dependent and -independent behavioral deficits in Tg2576 mice. Behav Brain Res 2008;189:126-38] we found that very few cognitive tests were suitable for demonstrating deficits in Tg2576 mice, an amyloid over-expression model of Alzheimer's disease, even at 23 months of age. However, in a retrospective analysis of a separate project on these mice, tests of social memory and open field habituation revealed large cognitive impairments. Controls showed good open field habituation, but Tg2576 mice were hyperactive and failed to habituate. In the test of social memory for a juvenile mouse, controls showed considerably less social investigation on the second meeting, indicating memory of the juvenile, whereas Tg2576 mice did not show this decrement.As a control for olfactory sensitivity, on which social memory relies, the ability to find a food pellet hidden under wood chip bedding was assessed. Tg2576 mice found the pellet as quickly as controls. As this test requires digging ability, this was independently assessed in tests of burrowing and directly observed digging. In line with previous results and the hippocampal dysfunction characteristic of aged Tg2576 mice, they both burrowed and dug less than controls.

Sub-pyrogenic systemic inflammation impacts on brain and behavior, independent of cytokines.

Systemic inflammation impacts on the brain and gives rise to behavioral changes, often referred to as 'sickness behavior'. These symptoms are thought to be mainly mediated by pro-inflammatory cytokines. We have investigated the communication pathways between the immune system and brain following sub-pyrogenic inflammation. Low grade systemic inflammation was induced in mice using lipopolysaccharide (LPS); 1-100 microg/kg to mimic aspects of bacterial infection. Changes in fever, open-field activity, burrowing and consumption of glucose solution were assessed and immune activation was studied in the periphery and brain by measuring cytokine production, and immunohistochemistry to study changes in immune cell phenotype. Sub-pyrogenic inflammation resulted in changes in a species-typical, untrained behavior (burrowing) that depends on the integrity of the hippocampus. Increased expression of cytokines was observed in the periphery and selected regions of the brain which coincided with changes in behavior. However, peripheral neutralization of LPS-induced pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha did not abrogate the LPS-induced behavioral changes nor affect CNS cytokine synthesis. In contrast, pretreatment of mice with indomethacin completely prevented LPS-induced behavior changes, without affecting cytokine levels. Taken together, these experiments suggest a key role for prostaglandins, rather than cytokines, in communicating to the brain.