Visual Abstract

Electrophysiological and lesion studies in rodents have shown that the dorsal (septal) and ventral (temporal) segments of the hippocampus have functional specializations that can be understood in terms of their anatomical connections with distinct brain areas. Here we explore the circuitry associated with the hippocampus using the pseudorabies virus-Bartha strain (PRV-Bartha) tracer in the rat to examine both direct (first-order) and indirect (second-order) projections to the hippocampus. Based on analysis of PRV-Bartha infection density, we demonstrate two parallel pathways from the limbic cortex to the hippocampus. A dorsal "spatial cognition" pathway provides disynaptic input from the retrosplenial, anterior cingulate, and orbital cortex to the dorsal hippocampus, with potential synaptic relays in the anterior thalamic nuclei and dorsolateral entorhinal cortex. A ventral "executive control" pathway provides disynaptic input from the prelimbic, infralimbic, and orbital cortex to the ventral hippocampus, with potential synaptic relays in the midline thalamic nuclei and the rostral caudomedial entorhinal cortex. These data suggest a new anatomical framework for understanding the functional interactions between the cortex and hippocampus, especially in cognitive disorders that involve both structures, such as frontotemporal dementia.

The cerebral cortex, with all its computational power, can only influence behavior via corticofugal connections originating from layer 5 (L5) cells (Sherman and Guillery, 2013). To begin to establish the global pattern of these outputs, we examined L5 efferents originating from four cortical areas: somatosensory, visual, motor, and prefrontal (i.e., ventromedial orbitofrontal) cortex. We injected Cre-dependent adeno-associated virus in an Rbp4-Cre transgenic mouse line (both sexes) to label these L5 efferents selectively. Our study reveals that, across this diverse series of cortical regions, L5 commonly projects to multiple thalamic and extrathalamic sites. We also identified several novel corticofugal targets (i.e., the lateral dorsal nucleus, submedial nucleus) previously unidentified as L5 targets. We identified common patterns for these projections: all areas innervated both thalamus and the midbrain, and all areas innervated multiple thalamic targets, including those with core and matrix cell types (Jones, 1998). An examination of the terminal size within each of these targets suggests that terminal populations of L5 efferents are not consistently large but vary with cortical area and target; and in some cases, these include small terminals only. Overall, our data reveal more widespread and diverse L5 efferents than previously appreciated, suggesting a generalizable role for this cortical layer in influencing motor commands and cognitive processes.

On account of its strong efferent projections to the hippocampus, recent animal studies have emphasized an important role for the nucleus reuniens (NRe) of the midline thalamus in spatial memory. However, by virtue of its reciprocal connections with the orbital and ventromedial prefrontal cortex, the NRe may also be involved in aspects of executive inhibition. To date, there has been no systematic attempt to examine the role of the NRe in inhibitory mechanisms of response control. Accordingly, we compared rats with neurotoxic lesions of the NRe with sham surgery controls on performance of the 5-choice reaction time task, a test of visuospatial attention and inhibitory control. When tested post-operatively, rats with NRe lesions were unable to actively inhibit premature responses when the intertrial interval was varied. However, the same rats with NRe lesions showed normal inhibition of perseverative responses, and under some conditions were less perseverative than shams. The NRe lesion was also associated with a reduction in omissions and fast reward collection latencies, which persisted 2 months following surgery. The NRe lesion did not affect response accuracy or latency to respond correctly throughout the course of experimental testing. Together, these results signify the important role of the NRe in impulse inhibition, especially when slight changes are made to the temporal demands of the environment, and reveal the potential contribution of the NRe in motivational processes.

The role of the thalamus in complex cognitive behavior is a topic of increasing interest. Here we demonstrate that lesions of the nucleus reuniens (NRe), a midline thalamic nucleus interconnected with both hippocampal and prefrontal circuitry, lead to enhancement of executive behaviors typically associated with the prefrontal cortex. Rats were tested on four behavioral tasks: (1) the combined attention-memory (CAM) task, which simultaneously assessed attention to a visual target and memory for that target over a variable delay; (2) spatial memory using a radial arm maze, (3) discrimination and reversal learning using a touchscreen operant platform, and (4) decision-making with delayed outcomes. Following NRe lesions, the animals became more efficient in their performance, responding with shorter reaction times but also less impulsively than controls. This change, combined with a decrease in perseverative responses, led to focused attention in the CAM task and accelerated learning in the visual discrimination task. There were no observed changes in tasks involving either spatial memory or value-based decision making. These data complement ongoing efforts to understand the role of midline thalamic structures in human cognition, including the development of thalamic stimulation as a therapeutic strategy for acquired cognitive disabilities (Schiff, 2008; Mair et al., 2011), and point to the NRe as a potential target for clinical intervention.