Retrograde amnesia following disruptions of hippocampal function is often temporally graded, with recent memories being more impaired. Evidence supports the existence of one or more neocortical long-term memory storage/retrieval site(s). Neurotoxic lesions of the medial prefrontal cortex (mPFC) or the dorsal hippocampus (DH) were made 1 day or 200 days following trace fear conditioning. Recently encoded trace fear memories were most disrupted by DH lesions, while remotely encoded trace and contextual memories were most disrupted by mPFC lesions. These data strongly support the consolidation theory of hippocampus function and implicate the mPFC as a site of long-term memory storage/retrieval.The consolidation of memories into their long-term, stabilized form is a topic of considerable theoretical and empirical scientific inquiry (McGaugh 2000;Squire et al. 2004;Frankland and Bontempi 2005;Wiltgen et al. 2005a). Independent brain circuits underlie different forms of memory, and, within a particular memory domain, the contribution of a specific region may depend upon the age of that memory (Ribot 1882;Squire 1992;Knowlton and Fanselow 1998;Frankland and Bontempi 2005).Consolidation theory suggests that memories are gradually reorganized such that the brain regions responsible for the storage/retrieval of a memory are changed (Marr 1971;McClelland et al. 1995;Squire and Alvarez 1995). Early evidence for this came from the characteristic pattern of temporally graded retrograde amnesia for declarative memories in human patients who had suffered insult to the medial temporal lobe (e.g., Scoville and Milner 1957). Similar patterns have been observed in animals using more circumscribed manipulations of the hippocampus across a variety of procedures, including object discrimination (Zola-Morgan and Squire 1990), contextual fear conditioning (Kim and Fanselow 1992;Anagnostaras et al. 1999), trace eyeblink conditioning (Kim et al. 1995;Takehara et al. 2002), and social transmission of food preference (Clark et al. 2002).In recent years, a shift has occurred toward identifying extrahippocampal regions that support long-term memories, and the medial prefrontal cortex (mPFC) has been implicated. The hippocampus and mPFC are functionally interrelated through correlated activity patterns that may be important for memory consolidation ( We assessed the role of the dorsal hippocampus (DH) and mPFC in trace and contextual fear memories. DH involvement in both trace and contextual fear conditioning has been previously demonstrated (e.g., McEchron et al. 1998;Quinn et al. 2002Quinn et al. , 2005Chowdhury et al. 2005). While a temporally graded retrograde amnesia for contextual fear conditioning is well established (e.g., Kim and Fanselow 1992;Anagnostaras et al. 1999), a similar assessment of trace fear conditioning has not yet been made. This experiment allows us to assess temporal gradients for two hippocampus-dependent memories within the same animal and determine whether the mPFC serves as a permanent storage/retrieval site for t...

Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein coded for by DTNBP1, dysbindin, is expressed within forebrain glutamatergic neurons, where it interacts with proteins involved in vesicular trafficking and exocytosis. In order to further delineate the cellular, physiological and behavioral phenotypes associated with reduced dysbindin expression, we conducted studies in mice carrying a null mutation within the dtnbp1 gene. Dysbindin mutants exhibited impairments of spatial working memory as compared with wild-type controls; heterozygous mice exhibited intermediate levels of cognitive dysfunction. Deep layer pyramidal neurons recorded in the prefrontal cortex of mutant mice exhibited reductions in paired-pulse facilitation, and evoked and miniature excitatory post-synaptic currents, indicating a difference in the function of pre-synaptic glutamatergic terminals, as well as elevated spike thresholds. Taken together, these data indicate that dysbindin potently regulates excitatory transmission in prefrontal cortex, potentially through a pre-synaptic mechanism, and consequently modulates cognitive functions depending upon this brain region, providing new insights into the molecular mechanisms underlying cortical dysfunction in schizophrenia.

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The hippocampus is important for the formation of spatial, contextual, and episodic memories. For instance, lesions of the dorsal hippocampus (DH) produce demonstrable deficits in contextual fear conditioning. By contrast, it is generally agreed that the DH is not important for conditioning to a discrete cue (such as a tone or light) that is paired with footshock in a temporally contiguous fashion (delay conditioning). There are, however, some reports of hippocampus involvement in delay conditioning. The present series of experiments was designed to assess the conditions under which the hippocampus-dependent component of delay fear conditioning performance may be revealed. Here, we manipulated the number of conditioning trials and the intensity of the footshock in order to vary the strength of conditioning. The results indicate that the DH contributes to freezing performance to a delay conditioned tone when the conditioning parameters are relatively weak (few trials or low footshock intensity), but not when strong parameters are used. The results are discussed in terms of two parallel memory systems: a direct tone-footshock association that is independent of the hippocampus and a hippocampus-dependent memory for the conditioning session.