Early behavioural changes in scrapie-affected mice and the influence of dapsone

Behavioural testing can reveal effects in scrapie-infected mice long before overt clinical signs appear (Betmouni et al., 1999, Psychobiology, 27, 63–71). These effects may be partly attributable to an early, atypical inflammatory response in the brain (Betmouni et al., 1996, Neuroscience, 74, 1–5). The present study replicated and extended these findings, and examined the effect of chronic treatment with dapsone. This anti-inflammatory compound has been reported to delay disease onset in a rat model of Creutzfeldt–Jakob disease (Manuelidis et al., 1998, Lancet, 352, 456). Although the doses used in the present study were higher than those of Manuelidis et al. (1998), no attenuation of the disease was seen in either behavioural or subsequent histological tests. Burrowing, i.e. displacing food pellets from a tube in the home cage, decreased from around week 12 in scrapie-infected mice, as did consumption of palatable glucose solution. Concurrently, ambulation in an open field increased, as did rearing at around week 17. Spontaneous alternation was impaired around this time. Around 18 weeks, motor performance on an inverted screen, horizontal bar, rotating rod and static rods decreased. Nest construction was impaired at 20 weeks. Overt clinical signs (reduction in mobility, hunched posture, poor coat condition, bladder enlargement) only occurred after week 20, when the mice were prepared for histology. The ME7 scrapie-infected mice thus showed a characteristic complex of neurological and behavioural changes during the course of the disease that were not ameliorated by dapsone. These changes appeared well before clinical signs were prominent

Hippocampal scrapie infection impairs operant DRL performance in mice

In differential reinforcement of low rates of responding (DRL) tasks, animals are trained to respond for rewards that become available only after some set time has elapsed since the animal's previous response. DRL performance is impaired by hippocampal lesions regardless of their precise location, and can be measured using automated operant equipment, whereas spatial tasks are selectively impaired by dorsal, but not ventral hippocampal lesions, and are typically conducted by hand. Earlier studies of prion infection following dorsal hippocampal microinjections of scrapie have shown clear impairments of spatial alternation, but these occurred significantly later than dysfunction in hippocampus-dependent domestic tasks such as nesting or burrowing. In the present experiment, mice were trained to respond on an automated DRL schedule prior to dorsal hippocampal ME7 scrapie injection. Postoperative DRL performance was monitored, along with performance on domestic and other tests, which provided additional measures of disease progression. Animals with scrapie developed a clear DRL deficit at approximately the same time as their deficits on the other tests became apparent, and long before clinical signs were detectable. DRL deficits thus appeared earlier in the sequence of disease progression than previously reported for spatial alternation, suggesting that early signs of scrapie infection are caused in part by neuronal dysfunction extending beyond the dorsal hippocampal region of initial infection

A double dissociation between the effects of sub-pyrogenic inflammation and hippocampal lesions on learning

Immune system activation has been found to affect the function of the hippocampus. Sub-pyrogenic systemic inflammation impairs performance of species-typical behaviours that are also disrupted by hippocampal lesions in rodents. In a series of experiments the effect of a low, sub-pyrogenic dose of lipopolysaccharide (LPS) on hippocampus-dependent learning and memory was tested. LPS failed to impair hippocampus-dependent spatial reference memory and working memory. However, LPS affected learning a simple side-discrimination task in which an arm of a T-maze was rewarded (correct arm), and the other arm was never rewarded (incorrect arm). Whereas LPS actually enhanced performance when reward was available on every trial in the correct arm, LPS impaired learning when the correct arm was rewarded on 50% of trials. Hippocampal lesions did not impair either the continuous or partial reinforcement versions of the task. These results demonstrate that a low, sub-pyrogenic dose of LPS can impair cognitive function, but can, depending on the demands of the task, also facilitate learning. However, the double dissociation between the effects of LPS and hippocampal lesions demonstrate that sub-pyrogenic inflammation does not affect learning by disrupting hippocampal function.<br/

Hippocampal lesions can enhance discrimination learning despite normal sensitivity to incidental information

Spatial properties of stimuli are sometimes encoded even when incidental to the demands of a particular learning task. Incidental encoding of spatial information may interfere with learning by (i) causing a failure to generalize learning between trials in which a cue is presented in different spatial locations and (ii) adding common spatial features to stimuli that predict different outcomes. Hippocampal lesions have been found to facilitate acquisition of certain tasks. This facilitation may occur because hippocampal lesions impair incidental encoding of spatial information that interferes with learning. To test this prediction mice with lesions of the hippocampus were trained on appetitive simple simultaneous discrimination tasks using inserts in the goal arms of a T-maze. It was found that hippocampal lesioned mice were facilitated at learning the discriminations, but they were sensitive to changes in spatial information in a manner that was similar to control mice. In a second experiment it was found that both control and hippocampal lesioned mice showed equivalent incidental encoding of egocentric spatial properties of the inserts, but both groups did not encode the allocentric information. These results demonstrate that mice show incidental encoding of egocentric spatial information that decreases the ability to solve simultaneous discrimination tasks. The normal egocentric spatial encoding in hippocampal lesioned mice contradicts theories of hippocampal function that suggest that the hippocampus is necessary for incidental learning per se, or is required for modulating stimulus representations based on the relevancy of information. The facilitated learning suggests that the hippocampal lesions can enhance learning of the same qualitative information as acquired by control mice

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 ?g/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-1?, IL-6 and TNF-? 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

NNZ-2566, a novel analog of (1-3) IGF-1, as a potential therapeutic agent for fragile X syndrome

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, and many agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. In the present work, a novel pharmacological approach for FXS is investigated. NNZ-2566, a synthetic analog of a naturally occurring neurotrophic peptide derived from insulin-like growth factor-1 (IGF-1), was administered to fmr1 knockout mice correcting learning and memory deficits, abnormal hyperactivity and social interaction, normalizing aberrant dendritic spine density, overactive ERK and Akt signaling, and macroorchidism. Altogether, our results indicate a unique disease-modifying potential for NNZ-2566 in FXS. Most importantly, the present data implicate the IGF-1 molecular pathway in the pathogenesis of FXS. A clinical trial is under way to ascertain whether these findings translate into clinical effects in FXS patients

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.