The Possible Anatomy of Spatial Navigation

Blake S Porter and David K Bilkey (2015)

Department of Psychology, University of Otago, Dunedin, NZ

Brain Health Research Center, University of Otago, Dunedin, NZ

Correspondence: Blake S Porter –


In a recent study, Ito, Zhang, Witter, Moser, & Moser (2015) have helped to clarify the brain circuitry underlying goal-directed behaviour by examining trajectory-dependent firing (firing which is selective to a particular future trajectory) in a continuous alternating t-maze task. They show that this predictive firing occurs in a subset of cells in dorsal CA1 (dCA1) of the hippocampus, in nucleus reuniens, and in medial prefrontal cortex (dorsal anterior cingulate and dorsal prelimbic), suggesting that these regions are part of a circuit for directing spatial navigation. The authors then go on to generate excitotoxic lesions in, or optogenetically inactivate, nucleus reuniens while recording dCA1 single unit activity. In the optogenetic group, nucleus reuniens units are also recorded. Lesioning nucleus reuniens resulted in a decrease in the percentage of trajectory-dependent dCA1 cells to a level similar to that observed in the CA3 region of control animals. Unlike CA1, CA3 does not receive direct inputs from the thalamus. Optogenetically inactivating nucleus reuniens also resulted in a decreased percentage of trajectory-dependent cells.  Learning and task performance were not altered by lesioning or inactivating nucleus reuniens. Ito, Zhang, Witter, Moser, & Moser (2015) propose that projections from the medial prefrontal cortex that project via the nucleus reuniens of the thalamus to the dorsal CA1 region of the hippocampus “are crucial for representation of the future path during goal-directed behavior”. While the results of this study are interesting and important, anatomical data suggests that the pathways involved may be more complex than are presented.

In a previous study, Prasad & Chudasama (2013) utilized pseudorabies virus-Bartha strain (a retrograde viral tracer that allows pathways to be followed transynaptically) to reveal the circuits linking the prefrontal cortex to the hippocampus. They confirmed that the pathway from prefrontal cortex to hippocampus is at least disynaptic and also show that different regions of the prefrontal cortex send information to the hippocampus via different anatomical pathways, which in turn synapse onto neurons within different subregions of the hippocampus. Their data indicates that two parallel pathways exist; a dorsal pathway (which they label a “spatial cognition” pathway) consists of fibres originating in the retrosplenial cortex, anterior cingulate (including dorsal anterior cingulate), and orbital prefrontal cortex that largely project via anterior thalamic nuclei (not nucleus reuniens) and the dorsolateral entorhinal cortex to terminate within the dorsal hippocampus, including in region CA1. A second pathway (described as an “executive function” pathway) runs parallel to the dorsal pathway but is more ventrally located. This ventral pathway begins in the prelimbic, infralimbic, and orbital cortex and largely projects via the midline thalamic nuclei (including nucleus reuniens) and the rostral caudomedial entorhinal cortex, to terminate within the ventral hippocampus. These two anatomical pathways map well onto the functional differences encountered along the dorsal-ventral axis of both the medial prefrontal cortex 3–5 and the hippocampus6–8.


figure 1_1



The anatomical data from Prasad & Chudasama (2013) suggest that lesioning or inactivating the nucleus reuniens alone will not prevent the transmission of future trajectory information from dorsal anterior cingulate and dorsal prelimbic cortex to dorsal CA1 (Figure 1). Rather, fibres originating from these two prefrontal regions primarily connect to dorsal CA1 via the anterior thalamic nuclei. Although the anterior thalamus was not directly targeted in the current study1, their histology of the excitotoxic lesion (Ito et al., 2015; Extended Data Figure 4) and optogenetic probe location (Ito et al., 2015; Extended Data Figure 6) suggest that anterior thalamic nuclei may have been affected by their interventions (especially for rat #16249, 16214; #17421, 18679). This suggests, that the role of the nucleus reuniens in mediating prefrontal-hippocampal communication may have been overstated by Ito, Zhang, Witter, Moser, & Moser (2015), and that a potential role for the dorsal pathway should be acknowledged.

The majority of the prefrontal cortical inputs to nucleus reuniens originate in the ventral prelimbic, infralimbic, and orbitofrontal cortex2. While these more ventrally located prefrontal cortices may be playing a role in providing the nucleus reuniens with future trajectory and goal related information, Ito, Zhang, Witter, Moser, & Moser (2015) do not collect single unit data from these structures and, therefore, we cannot know whether these regions display trajectory-dependent firing. Second, the nucleus reuniens largely innervates ventral, rather than dorsal, hippocampus. This poses the question as to why manipulations that disable the nucleus reuniens result in deficits in dorsal CA1. There is a small subset of nucleus reuniens cells that innervate dorsal CA1 (Prasad & Chudasama, 2013; Figure 4I). It is possible, therefore, that information encoded by the ventral prefrontal cortices and sent via nucleus reuniens influences trajectory-dependent firing of dorsal CA1 cells through this connection. Yet, the neurophysiological data show that a large proportion of neurons within the dorsally located anterior cingulate have trajectory-dependent firing9-11 and, when the comparison is made, this exceeds that observed in the ventrally-located prelimbic cortex neurons1. This further deepens the mystery as to why nucleus reuniens is needed for trajectory-dependent firing in dorsal CA1 and raises the question as to what additional information is conveyed to nucleus reuniens via ventral prefrontal structures that is not already provided through the dorsal pathway. Together, these data suggest that the combined information routed through both nucleus reuniens and anterior thalamic nuclei drives trajectory-dependent firing in dorsal CA1, rather than that which is transmitted through nucleus reuniens only.

To summarise, Ito, Zhang, Witter, Moser, & Moser’s (2015) conclusion “that projections from the medial prefrontal cortex, via the nucleus reuniens, are crucial for representation of the future path during goal-directed behavior” should be interpreted carefully for several reasons. First, the majority of projections from the prefrontal cortex to the dorsal CA1 subregion of the hippocampus connect via the anterior thalamus and not through nucleus reuniens. Second, the majority of projections from the nucleus reunions project to the ventral, rather than dorsal, CA1 subregion. Third, the majority of projections from the prefrontal cortex to nucleus reuniens originate in the ventral prelimbic, infralimbic, and orbitofrontal cortex, areas that the authors do not collect single unit data from. This suggests that the circuit from the medial prefrontal cortex to the hippocampus via the nucleus reuniens is likely to be just one part of the story regarding the pathways through which information about future spatial trajectories are communicated from prefrontal cortex to hippocampus.


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