Introduction
Changes in motivation, mood, and behavior are common early symptoms in human prion disorders, especially variant Creutzfeldt-Jakob disease (vCJD), often occurring long before diagnosis is made. By the time characteristic dementia and motor deficits are established, there is typically advanced neuronal loss, with no realistic potential for curative treatment or recovery. In experimentally infected mice, clinical disease is diagnosed by the presence of locomotor changes, but again, these occur during advanced disease and correspond with irreversible neuronal loss. However, there are earlier pathological and phenotypic changes. Spongiform change and synapse loss precede neuronal loss (Jeffrey et al., 2000), and changes in species-typical behaviors also occur long before typical motor symptoms (Betmouni et al., 1999, Cunningham et al., 2005, Deacon et al., 2001, Guenther et al., 2001) and correlate with early loss of presynaptic terminals in the dorsal hippocampus (Cunningham et al., 2003).

We previously showed that early spongiform degeneration in the hippocampus of prion-infected mice reverses when PrPC is depleted in neurons (Mallucci et al., 2003). We now ask whether this early pathological change produces functional deficits and whether its reversal is reflected in functional recovery. As the hippocampus is particularly targeted by several strains of murine prions and is easily accessible for neurophysiological measurements, we focused on tests of hippocampal function. We used prion-infected transgenic mice with and without “induced” PrP depletion for our experiments. Thus, tg37 mice express PrP from “floxed” PrP sequences (MloxP transgenes) and succumb to Rocky Mountain Laboratory (RML) prion infection ∼13 weeks postinoculation (wpi) (Mallucci et al., 2002). In these mice, earliest prion pathological changes, including spongiosis, gliosis, and PrPSc deposition, appear by 8 wpi (Mallucci et al., 2003). In double-transgenic NFH-Cre/tg37 mice, PrP expression is the same as in tg37 mice until floxed PrP sequences are excised by the DNA recombinase, Cre (Sauer et al., 1989), at ∼9–10 weeks of age, when neuronal PrP is depleted (Mallucci et al., 2002). NFH-Cre/tg37 mice infected with prions at 1 week of age develop early hippocampal pathology in parallel with control tg37 mice, but spongiosis reverses soon after Cre-mediated PrP depletion ∼8–9 wpi, and the animals survive long term (Mallucci et al., 2003).

We tested memory function and spontaneous ethological behaviors in vivo and measured synaptic responses neurophysiologically in vitro. We used the novel object recognition task, a nonspatial learning task based on the spontaneous preference of both mice and rats for novelty and their ability to remember previously encountered objects, that is rapidly learned (Clark et al., 2000, Dodart et al., 1997, Ennaceur et al., 1988, Messier, 1997). In rodents, the hippocampus is thought to be involved in delay-dependent object-recognition memory (i.e., when recognition intervals are long, >24 hr after learning phase), whereas recall over shorter retention intervals is thought to involve parahippocampal structures (Clark et al., 2000, Hammond et al., 2004, Mumby et al., 2005). Novel-object recognition is extensively used for testing declarative memory in mice, and, critically, performance is independent of mouse strain or genetic background, unlike most other memory tasks for which performance is highly strain dependent (Sik et al., 2003). We also tested the spontaneous behaviors of burrowing and nesting, which have a robust association with early prion pathology (Betmouni et al., 1999, Cunningham et al., 2005, Deacon et al., 2001, Guenther et al., 2001) and also localize to the dorsal hippocampus. These behaviors have been proposed as powerful tools for elucidating brain function (Gerlai et al., 1999), requiring a high degree of organization and executive function, and are thought to reflect motivational aspects of spontaneous behavior in rodents.

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