These data suggest that theta-locked prelimbic neurons fire

immediately after the hippocampal neurons. Toward the end of the second postnatal week the firing rate of prelimbic neurons significantly augmented, reducing the risk ISRIB mouse of spurious cross-covariance (Figure 6B versus 6A). In prejuvenile rats 99 out of 878 prelimbic-hippocampal cell pairs were used for further analysis after excluding neurons with firing rate <0.05 Hz. The spiking relationship between prelimbic and hippocampal cells changed, subsets of prelimbic neurons firing either before or after the hippocampal ones. Consequently, significant Qi,j detected in 63 pairs showed peak lags between −50 and 0 ms as well as between 0 and 100 ms (Figure 6Bii). The spike-timing

relationship between prejuvenile prelimbic and hippocampal neurons confirms the theta-modulated mutual interactions between the two Neratinib in vitro areas. The concept of Granger causality is statistical in nature and therefore, the causal influence of the Hipp on the PL does not imply that the hippocampal networks drive the prefrontal circuits by direct axonal pathways. More supportive of this hypothesis are the spike-timing relationships between prefrontal and hippocampal neurons (Qi,j peaks at max ± 100 ms time lag). While strong unidirectional and monosynaptic projections from intermediate/ventral Hipp innervate the adult PFC (Hoover and Vertes, 2007), no experimental findings

document their ingrowth through postnatal development. To assess this issue, we injected bilaterally small amounts of the retrograde tracer Fluorogold (FG) into the PFC of P1 (n = 4) and P6 (n = 2) rat pups. The spreading of tracer over the entire neonatal PFC precluded reliable distinction between hippocampal innervation of the Cg and PL (Figures 7A and S6). Six to thirteen days after FG injection, labeled cells were found predominantly in the CA1 area of the intermediate and ventral Hipp, their number else increasing until the end of the second postnatal week. Occasionally weaker staining of the CA3 area (n = 3 pups), subiculum (n = 4 pups), or dorsal Hipp (n = 1 pup) as well as of the entorhinal cortex (EC) (n = 5 pups) could be detected. To identify the contribution of these direct hippocampal projections to the generation of oscillatory activity in the Cg and PL, the hippocampal CA1 area was electrically stimulated using a bipolar electrode (Figure S7A). Its insertion did not impair the cingulate or prelimbic oscillatory activity (n = 3 pups) (Figure S8). Single stimulation of the CA1 area evoked direct responses in the Cg and PL that started simultaneously after 12.2 ± 0.6 ms (n = 6 pups) and lasted 22.34 ± 1.71 ms and 23 ± 1.88 ms, respectively. In 3 out of 6 P7–9 rats the direct response was followed by network oscillations in 13.11% ± 4.