Yoshinori Izaki

Specific role of the posterior dorsal hippocampus–prefrontal cortex in short-term working memory

Working memory in rats involves neural projections from the hippocampus (HP) to the prefrontal cortex (PFC), based on delayed task experiments in a radial‐arm maze, in which the time span of working memory is longer than seconds. To determine whether the HP–PFC pathway is involved in short‐term (on the order of seconds) working memory function, we lesioned the PFC and/or HP, and measured performance in an operant delayed alternation task. The posterior dorsal (pdHP) and ventral HP (vHP) were assessed separately. The bilateral PFC and bilateral pdHP ibotenate lesions produced significant working memory deficits, but the vHP lesion did not. Unilateral pdHP lesions combined with a PFC lesion in the opposite hemisphere reproduced the effects of bilaterally symmetrical lesions. By contrast, unilateral lesions of the pdHP combined with a PFC lesion in the same hemisphere had no effect on delayed alternation. These results indicate that the pdHP–PFC pathway is essential for working memory on the order of seconds in rats, and suggest that the pdHP and vHP pathways to the PFC play different behavioral roles.

Differences between paired-pulse facilitation and long-term potentiation in the dorsal and ventral hippocampal CA1-prefrontal pathways of rats

We studied the interaction between paired-pulse facilitation (PPF) and long-term potentiation (LTP) in the hippocampo-prefrontal cortex (PFC, prelimbic area) pathway, stimulating the ventral or posterior dorsal CA1 region (vCA1 or pdCA1). In the vCA1-PFC, the group averaged PPF did not change after the LTP induction, and there was a negative correlation between the post-LTP PPF change and LTP magnitude. In contrast, the post-LTP PPF of the pdCA1-PFC appeared to decrease significantly, and the PPF change was independent of the LTP magnitude. We found that there were at least two mechanisms of PPF regulation following LTP induction in the pathway resulting from extensive CA1 projections into the prelimbic area. The results imply that the CA1-PFC pathway regulates the PFC PPF quantitatively in LTP-dependent and independent manners, which depend on the local properties of the CA1 regions.

Cooperativity between hippocampal–prefrontal short-term plasticity through associative long-term potentiation

The hippocampal-medial prefrontal cortex (mPFC) pathway provides highly convergent input to the mPFC in rats and shows two types of short-term plasticity in terms of paired-pulse facilitation (PPF) of the field potential under urethane anesthesia. We now report that stimulating either the dorsal or ventral subregions of the posterior hippocampus elicited PPF (by about 335 and 120%, respectively) of field potentials recorded in the mPFC at 100 ms interpulse interval. This PPF-like interaction occurred when projections were stimulated in the ventral-dorsal order (by about 200% of the single-pulsed response), but not vice versa. When weak long-term potentiation (LTP) of the dorsal projection was evoked simultaneously with strong LTP of the ventral projection, an associative effect was revealed (about +55%), although the magnitudes of LTP in each projection were not correlated. Even when the impermutable PPF-like facilitation was further enhanced (by about +120%), the enhancement was not correlated with either form of LTP, but exhibited the interaction of changes in the dorsal PPF, rather than in the heterotopic priming effect through the ventral projection. Moreover, this change was correlated with the associated LTP ratio of dorsal to ventral projection LTP (i.e., LTP associativity). Larger increases in LTP associativity correlated with greater impermutable PPF-like facilitation; in addition, there was hardly attenuation of the response to the dorsal projection by subsequent electrolytic lesions of the ventral subregion. These results indicate that the mPFC functionally integrates discrete sources of hippocampal information via cooperativity between short- and long-term plasticity.

Compatibility of bidirectional synaptic plasticity on hippocampo-prefrontal cortex pathway in rats

The hippocampo-prefrontal cortex pathway reportedly expresses long-term potentiation (LTP) and depression (LTD) in anesthetized rats. We examined whether there were any effects governing the induction of LTD after prior induction of LTP, or vice versa. Induction in sequence of LTP and LTD resulted in significantly stable changes of about 140 and 70% of a common control for 1 h each. The reversed sequence, LTD and LTP, showed a mirror image of about 65 and 135% of control, which were not different from the respective changes in the first sequence (P>0.3 for each). The correlation coefficient between changes was significantly positive in the first sequence and weakly negative in the reverse. These results indicate that this pathway can express compatibility of bidirectional synaptic plasticity while historical changes remain covert.

In vivo temporal property of GABAergic neural transmission in collateral feed-forward inhibition system of hippocampal–prefrontal pathway

Anatomical evidence suggests that rat CA1 hippocampal afferents collaterally innervate excitatory projecting pyramidal neurons and inhibitory interneurons, creating a disynaptic, feed-forward inhibition microcircuit in the medial prefrontal cortex (mPFC). We investigated the temporal relationship between the frequency of paired synaptic transmission and gamma-aminobutyric acid (GABA)ergic receptor-mediated modulation of the microcircuit in vivo under urethane anesthesia. Local perfusions of a GABAa antagonist (-)-bicuculline into the mPFC via microdialysis resulted in a statistically significant disinhibitory effect on intrinsic GABA action, increasing the first and second mPFC responses following hippocampal paired stimulation at interstimulus intervals of 100-200 ms, but not those at 25-50 ms. This (-)-bicuculline-induced disinhibition was compensated by the GABAa agonist muscimol, which itself did not attenuate the intrinsic oscillation of the local field potentials. The perfusion of a sub-minimal concentration of GABAb agonist (R)-baclofen slightly enhanced the synaptic transmission, regardless of the interstimulus interval. In addition to the tonic control by spontaneous fast-spiking GABAergic neurons, it is clear the sequential transmission of the hippocampal-mPFC pathway can phasically drive the collateral feed-forward inhibition system through activation of a GABAa receptor, bringing an active signal filter to the various types of impulse trains that enter the mPFC from the hippocampus in vivo.

Effects of acetylcholine antagonist injection into the prefrontal cortex on the progress of lever-press extinction in rats

To determine the relationship between cholinergic modulation within the rat medial prefrontal cortex (mPFC) and the progress of lever-press extinction, we conducted an experiment in which muscarinic and nicotinic acetylcholine (ACh) receptor antagonists were microinjected into the mPFC. The muscarinic antagonist injected immediately before the initial extinction training did not affect the progress of extinction during the training (no within-session effect), but disrupted a second re-training session the next day (across-session effect). By contrast, the nicotinic antagonist disrupted the progress of extinction both within and across training sessions. These results confirm that ACh in the mPFC modulates lever-press extinction and suggest that nicotinic and muscarinic receptors are involved in short- and long-term memory processes.

Functional structure of the intermediate and ventral hippocampo-prefrontal pathway in the prefrontal convergent system.

The hippocampo-prefrontal pathway is a unique projection that connects distant ends of the cerebral cortex. The direct hippocampo-prefrontal projection arises from the ventral to intermediate third of the hippocampus, but not from the dorsal third. It forms a funnel-shaped structure that collects information from the large hippocampal area and projects it to the prefrontal cortex. The anatomical regional differentiation of the projection has not been described. The hippocampal region is differentiated into structural and behavioural roles. For example, it has been shown that the ventral, but not the dorsal, hippocampus reciprocally connects with the amygdala and influences emotional behaviours. These data imply that hippocampal variation along the dorso-ventral axis is contained within the hippocampo-prefrontal pathway. Here, we present electrophysiological studies that demonstrate regional differences in short- but not long-term plasticity in the intermediate/posterior-dorsal and ventral routes of the hippocampo-prefrontal pathway. Furthermore, behavioural studies revealed that each route appears to play a different role in working memory. These results suggest that hippocampal regional information is processed through different routes, with the integration of individual regulatory functions in the prefrontal convergent system.

Evoked prefrontal gamma oscillation by hippocampal train stimulation in anesthetized rats.

We previously reported a difference in short-term synaptic plasticity between the rat posterior dorsal CA1 (pdCA1)-prefrontal cortex (PFC) and ventral CA1 (vCA1)-PFC pathways. Here, to determine the effects of hippocampal train stimulation on the local field potential in the medial PFC, we recorded the PFC field potential with brief 250-Hz train stimulation (1, 3, 5, 7, and 9 pulses) of pdCA1 or vCA1 in anesthetized rats. Analysis of the gamma-band (40-100 Hz) power revealed stimulation-evoked gamma oscillation in the pdCA1-PFC, but not in the vCA1-PFC. These results indicate that these pathways have different responses to train stimulation. The function of the pdCA1-PFC may differ from that of the vCA1-PFC, a well-known hippocampus-PFC pathway.

Effects of hippocampus-induced prefrontal long-term depression on gamma-band local field potential in anesthetized rats

To determine whether long-term depression (LTD) affects cortical gamma-band local field potential (40-100 Hz), we conducted a LTD induction experiment in the hippocampus-prefrontal cortex (PFC) pathway of an anesthetized rat. The LTD induction increased the spontaneous level of PFC gamma-band power of 70-100 Hz, which was not affected after the long-term potentiation (LTP) induction in our previous experiment. In addition, the LTD induction increased the evoked PFC gamma-band power at 900 ms after hippocampal test stimulation; this latency appeared to differ from that (500-700 ms) observed in our previous LTP experiment. The results indicate that the PFC field potential increases its gamma-band power following both LTP and LTD in the hippocampus-PFC pathway, which is involved in working memory. Particularly, the sustained increase by LTD may reflect a representation of working memory.

Extracellular level of basolateral amygdalar dopamine responding to reversal of appetitive-conditioned discrimination in young and old rats

Young and old rats, aged 3 and 24 months old, respectively, were conditioned to press a lever under lamp-on conditions for reward acquisition and lamp-off for no reward using a variable interval reinforcement schedule that averaged 15 s; i.e., the minimal requirement was 4 responses/min. Over a 30-day period, young and old groups showed increased response to lamp-on from 22 to 35/min and from 10 to 23/min, respectively, and shortened response to lamp-off after initial training. Response to lamp-on as a percentage of total response to lamp-on and -off (the discrimination ratio) was over 80%. For the next 30 days, reversal learning was imposed to reinforce discrimination of the lamp-off state. Young rats showed a steadily increasing discrimination ratio from 40% to 70%, and old rats from 30% to 60%. In comparison with the initial training, young rats showed a total response increase from 50% to 60%, while old rats showed an approximately 5% decrease without loss of reward-obtaining efficiency. In vivo microdialysis during reversal revealed that young rats had higher dopamine transmission in the basolateral amygdala than old rats. The dopamine level was positively correlated with the number of responses to state of reward in young rats and negatively with the numbers of both NRF and RF responses to lamp-on and -off states in old rats. These results suggest that in reversal discrimination, basolateral amygdalar dopamine efflux correlates with the manner of age-related conditioned response rather than the ability to learn.