Serotonergic modulation of hippocampal theta activity in relation to hippocampal information processing.

Hippocampal theta activity is the result of the concerted activity of a group of nuclei located in the brain stem and the caudal diencephalic area, which are together referred to as the synchronizing ascending system. Serotonin is recognized as the only neurotransmitter able to desynchronize the hippocampal electroencephalographic. A theory has been developed in which serotonin, acting on medial septal neurons, modulates cholinergic/GABAergic inputs to the hippocampus and, thus, the cognitive processing mediated by this area. However, few studies have addressed the relationship between serotonin modulation of theta activity and cognition. In this review, we present a summary and analysis of the data relating serotonin and its theta activity modulation with cognition, and we also discuss the few works relating serotonin, theta activity and cognition as well as the theories regarding the serotonin regulation of memory processes organized by the hippocampus. We propose that serotonin depletion induces impairment of the relays coding the frequency of hippocampal theta activity, whereas depletion of the relays in which frequency is not coded induces improvements in spatial learning that are related to increased expression of high-frequency theta activity.

Medial entorhinal cortex activates in a traveling wave in the rat.

Traveling waves are hypothesized to support the long-range coordination of anatomically distributed circuits. Whether separate strongly interacting circuits exhibit traveling waves remains unknown. The hippocampus exhibits traveling 'theta' waves and interacts strongly with the medial entorhinal cortex (MEC). To determine whether the MEC also activates in a traveling wave, we performed extracellular recordings of local field potentials (LFP) and multi-unit activity along the MEC. These recordings revealed progressive phase shifts in activity, indicating that the MEC also activates in a traveling wave. Variation in theta waveform along the region, generated by gradients in local physiology, contributed to the observed phase shifts. Removing waveform-related phase shifts left significant residual phase shifts. The residual phase shifts covaried with theta frequency in a manner consistent with those generated by weakly coupled oscillators. These results show that the coordination of anatomically distributed circuits could be enabled by traveling waves but reveal heterogeneity in the mechanisms generating those waves.

Serotonergic modulation of septo-hippocampal and septo-mammillary theta activity during spatial learning, in the rat.

Theta activity has been related to the processing of spatial information and the formation of hippocampus-dependent memory. The medial septum (MS) plays an important role in the control and coordination of theta activity, as well as in the modulation of learning. It has been established that increased serotonergic activity may desynchronize theta activity, while reduced serotonergic activity produces continuous and persistent theta activity in the hippocampus. We investigate whether serotonin acting on the medial septum could modify spatial learning and the functional relationship between septo-hippocampal and septo-mammillary theta activity. The serotonin was depleted (5HT-D) from the medial septum by the injection of 5,7 DHT (5,7- dihydroxytryptamine). Theta activity was recorded in the dorsal hippocampus, MS and mammillary nuclei (SUM, MM) of Sprague-Dawley male rats during spatial learning in the Morris water maze. Spatial learning was facilitated, and the frequency of the hippocampal theta activity during the first days of training increased (to 8.5Hz) in the 5HT-D group, unlike the vehicle group. Additionally, the coherence between the MS-hippocampus and the MS-mammillary nuclei was higher during the second day of the test compared to the vehicle group. We demonstrated that septal serotonin depletion facilitates the acquisition of spatial information in association with a higher functional coupling of the medial septum with the hippocampus and mammillary nuclei. Serotonin, acting in the medial septum, modulates hippocampal theta activity and spatial learning.

Hippocampal strata theta oscillations change their frequency and coupling during spatial learning.

The theta rhythm is necessary for hippocampal-dependent spatial learning. It has been proposed that each hippocampal stratum can generate a current theta dipole. Therefore, considering that each hippocampal circuit (CA1, CA3, and Dentate Gyrus (DG)) contributes differently to distinct aspects of a spatial memory, the theta oscillations on each stratum and their couplings may exhibit oscillatory dynamics associated with different stages of learning. To test this hypothesis, the theta oscillations from five hippocampal strata were recorded in the rat during different stages of learning in a Morris maze. The peak power, the relative power (RP) and the coherence between hippocampal strata were analyzed. The early acquisition stage of the Morris task was characterized by the predominance of slow frequency theta activity and high coupling between specific hippocampal strata at slow frequencies. However, on the last training day, the theta oscillations were faster in all hippocampal strata, with tighter coupling at fast frequencies between the CA3 pyramidal stratum and other strata. Our results suggest that modifications to the theta frequency and its coupling can be a means by which the hippocampus differentially operates during acquisition and retrieval states.

Supramammillary serotonin reduction alters place learning and concomitant hippocampal, septal, and supramammillar theta activity in a Morris water maze.

Hippocampal theta activity is related to spatial information processing, and high-frequency theta activity, in particular, has been linked to efficient spatial memory performance. Theta activity is regulated by the synchronizing ascending system (SAS), which includes mesencephalic and diencephalic relays. The supramamillary nucleus (SUMn) is located between the reticularis pontis oralis and the medial septum (MS), in close relation with the posterior hypothalamic nucleus (PHn), all of which are part of this ascending system. It has been proposed that the SUMn plays a role in the modulation of hippocampal theta-frequency; this could occur through direct connections between the SUMn and the hippocampus or through the influence of the SUMn on the MS. Serotonergic raphe neurons prominently innervate the hippocampus and several components of the SAS, including the SUMn. Serotonin desynchronizes hippocampal theta activity, and it has been proposed that serotonin may regulate learning through the modulation of hippocampal synchrony. In agreement with this hypothesis, serotonin depletion in the SUMn/PHn results in deficient spatial learning and alterations in CA1 theta activity-related learning in a Morris water maze. Because it has been reported that SUMn inactivation with lidocaine impairs the consolidation of reference memory, we asked whether changes in hippocampal theta activity related to learning would occur through serotonin depletion in the SUMn, together with deficiencies in memory. We infused 5,7-DHT bilaterally into the SUMn in rats and evaluated place learning in the standard Morris water maze task. Hippocampal (CA1 and dentate gyrus), septal and SUMn EEG were recorded during training of the test. The EEG power in each region and the coherence between the different regions were evaluated. Serotonin depletion in the SUMn induced deficient spatial learning and altered the expression of hippocampal high-frequency theta activity. These results provide evidence in support of a role for serotonin as a modulator of hippocampal learning, acting through changes in the synchronicity evoked in several relays of the SAS.

Septal serotonin depletion in rats facilitates working memory in the radial arm maze and increases hippocampal high-frequency theta activity.

Hippocampal theta activity, which is strongly modulated by the septal medial/Broca׳s diagonal band neurons, has been linked to information processing of the hippocampus. Serotonin from the medial raphe nuclei desynchronises hippocampal theta activity, whereas inactivation or a lesion of this nucleus induces continuous and persistent theta activity in the hippocampus. Hippocampal serotonin depletion produces an increased expression of high-frequency theta activity concurrent with the facilitation of place learning in the Morris maze. The medial septum-diagonal band of Broca complex (MS/DBB) has been proposed as a key structure in the serotonin modulation of theta activity. We addressed whether serotonin depletion of the MS/DBB induces changes in the characteristics of hippocampal theta activity and whether the depletion is associated with learning in a working memory spatial task in the radial arm maze. Sprague Dawley rats were depleted of 5HT with the infusion of 5,7-dihydroxytriptamine (5,7-DHT) in MS/DBB and were subsequently trained in the standard test (win-shift) in the radial arm, while the CA1 EEG activity was simultaneously recorded through telemetry. The MS/DBB serotonin depletion induced a low level of expression of low-frequency (4.5-6.5Hz) and a higher expression of high-frequency (6.5-9.5Hz) theta activity concomitant to a minor number of errors committed by rats on the working memory test. Thus, the depletion of serotonin in the MS/DBB caused a facilitator effect on working memory and a predominance of high-frequency theta activity.

Serotonin depletion of supramammillary/posterior hypothalamus nuclei produces place learning deficiencies and alters the concomitant hippocampal theta activity in rats.

Hippocampal theta activity is important for the acquisition of spatial information and is strongly influenced and regulated by extra-hippocampal inputs from the synchronising ascending system (SAS), which includes the supramammillary nucleus (SUMn) and the posterior hypothalamic nucleus (PHn). Together these nuclei play an important role in controlling the frequency encoding of theta activity and are innervated by serotonin synapses, which also regulate theta activity and learning abilities. The participation of the SUMn in place learning and modulation of hippocampal theta activity were recently shown; thus, we questioned whether serotonin acting on SUMn/PHn could modulate place learning ability and concurrent hippocampal theta activity. The serotonergic terminals of the SUMn/PHn in rats were lesioned through 5,7-dihydroxytryptamine (5,7-DHT) infusion, and hippocampal theta activity during the Morris water maze test was recorded. Rats in the vehicle group learned the task efficiently and showed learning-related theta changes in the CA1 and dentate gyrus regions throughout the training. The 5-HT-depleted rats were deficient in the Morris water maze task and showed theta activity in the CA1 and dentate gyrus that were unrelated to the processing of learning. We conclude that serotonin can regulate the hippocampal theta activity acting on the SUMn/PHn relay of the SAS and that the influence of 5-HT in these nuclei is required for the learning-related changes in hippocampal theta activity that underlie the successful resolution of the Morris water maze task.

Differential learning-related changes in theta activity during place learning in young and old rats.

The participation key role of the hippocampus in place learning ability as well as the decline of cognitive functions associated with aging, have been established in experimental and clinical studies. On the other hand, hippocampal theta activity has been proposed as a part of the cerebral phenomena underlying hippocampal-dependent learning processes. In the present study, the relative power of low, high, and maximal frequency components of hippocampal CA1 theta activity during a 6-day training period (four daily trials; basal, searching, and platform stages) and the probe trial of a place learning paradigm (Morris water maze) were analyzed in young and aged rats. An increase in high frequency, and a decrease in low frequency relative power of theta activity during the searching stage, which were correlated with shorter swimming path lengths and predominant hippocampal-dependent allocentric strategies, were observed in young rats as became trained in place learning and memory tasks, in the Morris water maze; while, under these conditions, no changes in theta activity and predominant non hippocampal-dependent egocentric strategies occurred in the old rats. Besides, an overall (theta activity recorded during the three behavioral stages) increase of low frequency and an overall decrease of high frequency theta bands in the old group as compared to the young group were observed. These electrophysiological data suggest that old rats process information relevant for cognitive functions in a different manner, possibly leading to the use of different learning strategies, than young rats.

Hippocampal serotonin depletion facilitates place learning concurrent with an increase in CA1 high frequency theta activity expression in the rat.

Acetylcholine- and serotonin-dependent theta activities have been long proposed to exist. However, several studies have shown that serotonin tends to desynchronise hippocampal EEG activity. Theta activity has been related to the processing of hippocampal place learning. Since the serotonergic system can influence hippocampal theta activity, it could function as a modulator of spatial learning. For these reasons, we investigated the possible role of hippocampal serotonin in the regulation of theta activity during the acquisition of map-based spatial information. Following 5-HT hippocampal depletion through 5,7-dihydroxytriptamine-induced lesions to the fimbria, fornix and cingulate bundle of adult rats, CA1 hippocampal theta activity was recorded during place learning training. Only rats with reduction higher than 90% from controls, verified post-mortem by HPLC were studied. A facilitation of place learning after hippocampal serotonin depletion occurred, and was associated with earlier expression of dominant high frequency theta activity (6.5-9.5Hz). Therefore, theta activity was related to the accuracy of behavioural performance through 5-HT modulation in a place learning test.