The main contributions of the present study to our functional understanding of the direct cortical projection to the CA1 subregion are threefold: (1) EC-CA1 synaptic transmission appears to play an active role in intermediate, but not short-term working memory and comparative match-mismatch processes underlying spatial novelty, but not object novelty detection. (2) The non-selective dopamine agonist, apomorphine appears to produce a disruption that is selective to the dorsal CA1 subregion and in CA1-dependent memory processes. This is in comparison to the observed absence of disruption after an injection of apomorphine into the CA3 subregion or overlying cortex. Minor effects observed for the CA3-control group in the novelty detection paradigm may be accounted for by diffusion of apomorphine from the CA3 injection site to CA1. These observations also indicate that the comparative match-mismatch process for memory guided exploration of visual objects and the spatial configuration of objects can be dissociated from the detection of novelty alone. (3) Lastly, the present data support a role for dopamine in modulating CA1 function.
Our data support the comparative match-mismatch operation in EC-CA1 circuitry that function to detect a mismatch in the current associative (i.e., spatial and visual object) input from previous input to determine novelty. Many computational models of hippocampal function that include a representation of CA1 implicate the subregion in a functional “comparator” operation between SC input and the direct cortical input [16
]. The input to CA1 via the SC axons of CA3 cells terminate in the proximal stratum radiatum (s. rad) layer, whereas the input from the direct pp projects from layer III of EC to the most distal dendrites of stratum lacunosum moleculare (s.l-m) [7
]. Recently, there has been clear physiological and neuromodulatory evidence for a differentiation between the SC and pp inputs into the CA1 subregion, further suggesting a need to functionally disambiguate the role of each projection. Electrophysiological studies both in vivo
and in vitro
have only recently begun to show the vital importance of the direct cortical input in models for CA1 function and provide increased support for comparative match-mismatch functions in this region [3
]. For example, restricted lesions that target the trisynaptic circuitry (CA3, DG) do not produce impairments in the development and stability of place cells in CA1, nor do such lesions produce deficits in place retention or recognition; however, targeted disruption to EC-CA1 circuitry produces deficits in retention and retrieval over intermediate-term delays and memory consolidation processes [3
]. There is evidence that the maintenance of behaviorally significant place-cell activity in CA1 is independent of trisynaptic input and can be controlled by frequency-dependent output from EC to CA1 and modulatory effects of EC-CA1 activity on SC efficacy and plasticity [3
]. These data are futher supported by reports of cellular and molecular activity in CA1 during the intermediate-term time delays involved in working memory (i.e., DNMP) and consolidation processes. For example, there is evidence for neural activity in CA1 firing differentially for match and nonmatch trials during a delay period for a delayed non-match-to-sample task [40
], and other data demonstrating increased expression of LTP-related immediate early genes (IEGs) (i.e., BDNF, zif268, c-FOS, & JUNB) in dorsal CA1 within 24 hr after the exposure to learning [1
]. These data suggest CA1 processes comparisons among relevant stimuli and abstractions of the relevant spatial relations of the stimuli during a delay period of up to 24 hr after learning in which the information may continue to be relevant.
The present study takes advantage of two paradigms in which the comparative match-mismatch function can be tested, such that infusion of apomorphine prior to performance of a spatial working memory or spontaneous exploration task produces deficits in spatial navigation and detection of spatial novelty. In the 8-arm maze, during a 5-min delay, the animal must actively maintain the representation of the study arm in which it received a food reward so that when presented with a choice, it may choose the non-match, or novel choice arm to receive the food reward. In the novelty detection paradigm, the animal actively maintains the configuration of objects during the approximately 15-min delay between Session 3 and 4 in which it receives apomorphine injections. Previous behavioral studies have demonstrated that disruption to EC-CA1 circuitry by either CA1 lesions, CA1 inactivation, glutamate receptor blockade, or by a dopamine agonist, produces deficits in retention and retrieval of spatial information relevant to maze navigation and context-associated fear [6
]. It appears that the computational process underlying the comparative match-mismatch operation in EC-CA1 is susceptible to disruption at a delay of at least 5-min and up to 24-hr, while sparing short-term or immediate recall, encoding, and thus acquisition of spatial information necessary for goal-directed navigation, and cue/context-associated fear. Accordingly, we propose that EC-CA1 synaptic function does not support comparative operations that involve habituation or detection of object novelty alone. It is likely that match-mismatch operations may be occurring during habituation and in the short-term, but the current data propose that dysfunction in the CA1 subregion vis-à-vis neurotoxic lesions or modification of synaptic activity between CA1 and EC vis-à-vis hyperdopaminergic states, disrupts only intermediate-term maintenance of contextual information necessary to detect configuration changes. When the spatial configuration does not change, as in habituation-1, -2, or of the re-exploration of non-displaced objects in the novelty detection task, no deficits are observed. Apparently, the effect of apomorphine in CA1 is capable of producing deficits in exploration only when there is a spatial change from expectation (i.e., spatial novelty) in the configuration. Similarly, when there is a change in context and associative input (i.e., visual object-place) is maintained, EC-CA1 does not appear to be necessary for performance. The current data indicate that apomorphine does not disrupt performance when rats are transferred to a novel 8-arm maze. We propose that the hippocampus may not be necessary for the comparator function, but that EC-CA1 function is specifically involved in the context in which the experience of a particular spatial configuration must be held in an intermediate-term memory (5 min – 24 hr) store and novelty based on associative information must be determined.
The current data from this series of behavioral experiments is supported by previous electrophysiological data that indicate apomorphine selectively modifies evoked responses in EC-CA1, while having little to no effect on the SC projection to CA1[57
]. Other studies have also shown dopamine to have a selective modulatory influence over the pp input to CA1 [9
]. The specific effects observed with apomorphine in CA1 are additionally supported by the findings that have localized dense mesencephalic projections and high levels of DA receptors in dendritic layers of CA1 that receive afferent input via the pp [2
]. Thus, the observed deficits are assumed to be attributed to apomorphine acting on those receptors specifically.
It has been suggested that increased availability of dopamine to a certain threshold within mesolimbic (i.e., VTA-hippocampus) circuitry may provide a means to disrupt or “switch” ongoing informational processes to allow for the initiation of, or detection of novel information processes [33
]. Depending on the level of dopamine, the “comparator” role of CA1 may essentially fluctuate between the computational algorithm necessary for either encoding or recall. Hasselmo and colleages propose specific encoding/retrieval dynamics [14
], in which a mismatch between SC- and EC-CA1 inputs would result in high levels of cholinergic modulation. This modulatory change supports the appropriate dynamics for learning, such that the autoassociative network in CA3 is strengthened and CA3-CA1 synaptic connectivity is suppressed. The Hasselmo model further suggests that EC-CA1 activity is necessary for context-dependent retrieval and proposes a role for dopamine in modulating the spatial and temporal context, which consists of a decaying store of prior associative object-place input [14
]. The current data supports Hasselmo’s model such that increases in dopamine availability in the CA1 region appears to interfere with the comparator match-mismatch function by interfering with the matching of information arriving via the SC input with the direct cortical input and reception of current sensory information. Thus, selective disruption of the pp input to CA1 will prevent proper detection of spatial novelty and alter the nature of processes underlying maintenance and retrieval of relevant spatial information.
In summary, this model of dopaminergic modulation has provided evidence to functionally differentiate the two projections into the CA1 subregion and facilitate the elucidation of hippocampal circuitry and its interaction with the entorhinal cortex. The present study showed deficits in two tasks that are apparently sensitive to CA1 dysfunction. These data are consistent with models of CA1 fulfilling a comparator role in detecting changes in spatial configurations and maintaining spatially relevant information for intermediate-term working memory, while sparing short-term working memory and detection of object novelty. The general effect of apomorphine leads us to assume that apomorphine acts directly on the pp input to CA1 and produces deficits in processing behaviorally-relevant sensory information. This model for isolating the CA1 region from receiving intact sensory information from cortex may also elucidate sensory processing deficits associated with dopaminergic hyperfunction and schizophrenia. Future studies may clarify the roles for different inputs to the hippocampus by developing more sophisticated models of spatio-temporal dynamics that involve interaction with the sensory environment during exploration and memory-guided behavior. Furthermore, specific lesion techniques that may allow one to selectively destroy pp fibers coming from EC Layer III and projecting to CA1 without producing seizure-like activity. Other studies may also test other neuromodulatory differences between the two projections to CA1 and thus continue to elucidate functional interactions between cortex and hippocampal subregions.