Projections of the hippocampal formation to the prefrontal cortex were visualized in the rat by means of the anterograde tracer Phaseolus vulgaris-leucoagglutinin. These projections distribute only to the prelimbic and the medial orbital cortices and arise exclusively from restricted portions of field CA1 of the Ammon's horn and the subiculum. The most dorsal portion of CA1 does not contribute fibers to this projection. In the subiculum, its origin is restricted to the proximal half, i.e., the portion that directly borders field CA1. Fibers from field CA1 and the subiculum have comparable distribution patterns in the prelimbic and medial orbital cortices. The density and distribution in the prefrontal cortex of the projections from the proximal portion of the subiculum depends on the location of the injections along the dorsoventral axis of the hippocampal formation: the intermediate portion of the subiculum projects more densely and diffusely than its dorsal and ventral portions. In the prelimbic cortex, labeled fibers are present in all layers, showing marked morphological differences in deep versus superficial layers. In layers V and VI, most of the fibers are vertically oriented, while in layers II and III they are short and oriented towards the pial surface. Although no clear differences in terminal distribution were observed along the rostrocaudal extent of the prelimbic cortex, its dorsal and ventral portions show different innervation patterns. In the ventral portion of the prelimbic cortex, varicose fibers and terminal arborizations were present in all cortical layers, deep (V and VI) as well as superficial (II and III). In its dorsal part, the innervation was less dense and mostly present in the deep layers (V and VI). The fiber and terminal distribution in the medial orbital cortex was diffuse in all layers with a slight preference for layers deep to layer II.

Research on the detrimental effects of stress in the brain has mainly focused on the hippocampus. Because prefrontal cortex (PFC) dysfunction characterizes many stress-related disorders, we here analyzed the impact of chronic stress in rats on the integrity of the hippocampal-PFC pathway, monitored by behavioral and electrophysiological function and morphological assessment. We show that chronic stress impairs synaptic plasticity by reducing LTP induction in the hippocampal-PFC connection; in addition, it induces selective atrophy within the PFC and severely disrupts working memory and behavioral flexibility, two functions that depend on PFC integrity. We also demonstrate that short periods of stress exposure induce spatial reference memory deficits before affecting PFC-dependent tasks, thus suggesting that the impairment of synaptic plasticity within the hippocampus-to-PFC connection is of relevance to the stressinduced PFC dysfunction. These findings evidence a fundamental role of the PFC in maladaptive responses to stress and identify this area as a target for intervention in stress-related disorders.

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