α7 nicotinic acetylcholine receptors induce long-term synaptic enhancement in the dorsal but not ventral hippocampus.

Agents that positively modulate the activity of α7nAChRs are used as cognitive enhancers and for the treatment of hippocampus-dependent functional decline. However, it is not known whether the expression and the effects of α7nAChRs apply to the entire longitudinal axis of the hippocampus equally. Given that cholinergic system-involving hippocampal functions are not equally distributed along the hippocampus, we comparatively examined the expression and the effects of α7nAChRs on excitatory synaptic transmission between the dorsal and the ventral hippocampal slices from adult rats. We found that α7nAChRs are equally expressed in the CA1 field of the two segments of the hippocampus. However, activation of α7nAChRs by their highly selective agonist PNU 282987 induced a gradually developing increase in field excitatory postsynaptic potential only in the dorsal hippocampus. This long-term potentiation was not reversed upon application of nonselective nicotinic receptor antagonist mecamylamine, but the induction of potentiation was prevented by prior blockade of α7nAChRs by their antagonist MG 624. In contrast to the long-term synaptic plasticity, we found that α7nAChRs did not modulate short-term synaptic plasticity in either the dorsal or the ventral hippocampus. These results may have implications for the role that α7nAChRs play in specifically modulating functions that depend on the normal function of the dorsal hippocampus. We propose that hippocampal functions that rely on a direct α7 nAChR-mediated persistent enhancement of glutamatergic synaptic transmission are preferably supported by dorsal but not ventral hippocampal synapses.

Region-Related Differences in Short-Term Synaptic Plasticity and Synaptotagmin-7 in the Male and Female Hippocampus of a Rat Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is an intellectual developmental disorder characterized, inter alia, by deficits in the short-term processing of neural information, such as sensory processing and working memory. The primary cause of FXS is the loss of fragile X messenger ribonucleoprotein (FMRP), which is profoundly involved in synaptic function and plasticity. Short-term synaptic plasticity (STSP) may play important roles in functions that are affected by FXS. Recent evidence points to the crucial involvement of the presynaptic calcium sensor synaptotagmin-7 (Syt-7) in STSP. However, how the loss of FMRP affects STSP and Syt-7 have been insufficiently studied. Furthermore, males and females are affected differently by FXS, but the underlying mechanisms remain elusive. The aim of the present study was to investigate possible changes in STSP and the expression of Syt-7 in the dorsal (DH) and ventral (VH) hippocampus of adult males and females in a Fmr1-knockout (KO) rat model of FXS. We found that the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D), two forms of STSP, as well as the expression of Syt-7, are normal in adult KO males, but the PPR is increased in the ventral hippocampus of KO females (6.4 ± 3.7 vs. 18.3 ± 4.2 at 25 ms in wild type (WT) and KO, respectively). Furthermore, we found no gender-related differences, but did find robust region-dependent difference in the STSP (e.g., the PPR at 50 ms: 50.0 ± 5.5 vs. 17.6 ± 2.9 in DH and VH of WT male rats; 53.1 ± 3.6 vs. 19.3 ± 4.6 in DH and VH of WT female rats; 48.1 ± 2.3 vs. 19.1 ± 3.3 in DH and VH of KO male rats; and 51.2 ± 3.3 vs. 24.7 ± 4.3 in DH and VH of KO female rats). AMPA receptors are similarly expressed in the two hippocampal segments of the two genotypes and in both genders. Also, basal excitatory synaptic transmission is higher in males compared to females. Interestingly, we found more than a twofold higher level of Syt-7, not synaptotagmin-1, in the dorsal compared to the ventral hippocampus in the males of both genotypes (0.43 ± 0.1 vs. 0.16 ± 0.02 in DH and VH of WT male rats, and 0.6 ± 0.13 vs. 0.23 ± 0.04 in DH and VH of KO male rats) and in the WT females (0.97 ± 0.23 vs. 0.31 ± 0.09 in DH and VH). These results point to the susceptibility of the female ventral hippocampus to FMRP loss. Importantly, the different levels of Syt-7, which parallel the higher score of the dorsal vs. ventral hippocampus on synaptic facilitation, suggest that Syt-7 may play a pivotal role in defining the striking differences in STSP along the long axis of the hippocampus.

Connectivity and Neuronal Synchrony during Seizures.

There is uncertainty regarding when and which groups of neurons fire synchronously during seizures. While several studies found heterogeneous firing during seizures, others suggested synchronous neuronal firing in the seizure core. We tested whether neuronal activity during seizures is orderly in the direction of the excitatory neuronal connections in the circuit. There are strong excitatory connections laterally within the septotemporally organized lamella and inhibitory trans-lamellar connections in the hippocampus, which allow testing of the connectivity hypothesis. We further tested whether epileptogenesis enhances synchrony and antiseizure drug administration disrupts it. We recorded local field potentials from CA1 pyramidal neurons using a small microelectrode array and kindled rats by a rapid, recurrent hippocampal stimulation protocol. We compared cross-correlation, theta phase synchronization, entropy, and event synchronization. These analyses revealed that the firing pattern was correlated along the lamellar, but not the septotemporal, axis during evoked seizures. During kindling, neuronal synchrony increased along the lamellar axis, while synchrony along the septotemporal axis remained relatively low. Additionally, the theta phase distribution demonstrated that CA1 pyramidal cell firing became preferential for theta oscillation negative peak as kindling progressed in the lamellar direction but not in the trans-lamellar direction. Last, event synchronization demonstrated that neuronal firings along the lamellar axis were more synchronized than those along the septotemporal axis. There was a marked decrease in synchronization and phase preference after treatment with phenytoin and levetiracetam. The synchrony structure of CA1 pyramidal neurons during seizures and epileptogenesis depends on anatomic connectivity and plasticity.SIGNIFICANCE STATEMENT We could improve the efficacy of brain stimulation to treat seizures by understanding the structure of synchrony. Electrical stimulation may disrupt seizures by desynchronizing neurons, but there is an uncertainty on which groups of neurons fire synchronously or chaotically during seizures. Here, we demonstrate that neurons linked by excitatory connections fire synchronously during seizures, and this synchrony is modulated by epileptogenesis and antiseizure drugs. Closed-loop brain stimulation carefully targeted to disrupt synchrony may improve the treatment of seizures.

Frequency-dependent layer-specific differences in short-term synaptic plasticity in the dorsal and ventral CA1 hippocampal field.

Information from the entorhinal cortex arrives to the hippocampal CA1 microcircuit directly through the temporoammonic path (TA) that terminates in the stratum lacunosum-moleculare (SLM), and indirectly through Schaffer collateral pathway (SC) that terminates in the stratum radiatum (SR). By virtue of this input convergence, CA1 circuitry may act to compare and integrate incoming cortical information. Although a remarkable dorsal-ventral difference in short-term plasticity (STP) has been recently described at SC-CA1 synapses, the corresponding properties at TA-CA1 synapses have not been examined. Here, we report that stimulation of TA in the dorsal hippocampus produces significant facilitation of all conditioned responses evoked by 1-30 Hz, peaking at 20-30 Hz, and significant depression of steady-state responses to 50-100 Hz. Dorsal SC-CA1 synapses display a similar pattern of responses, yet, facilitation peaked at 10 Hz and depression (at 75-100 Hz) is weaker. Strikingly, stimulation of TA in the ventral hippocampus produces facilitation of steady-state responses to 1-30 Hz and highly contrasts with the depression of SC-CA1 synapses. Steady-state responses to 40-100 Hz in the ventral hippocampus depress in both layers similarly. High-frequency TA input (40-100 Hz) to the dorsal hippocampus depresses more in proximal than in distal SLM, while low-frequency (1-3 Hz) TA input to the ventral hippocampus facilitates more in distal than in proximal SLM. The present evidence suggests that direct and indirect entorhinal cortical inputs across the septotemporal extent of hippocampal CA1 field display frequency selectivity both in the radial and transverse axes, and that a rapid information processing may take place through direct ventral hippocampal CA1-EC circuit interactions independently of trisynaptic circuit.

Differential propagation of ripples along the proximodistal and septotemporal axes of dorsal CA1 of rats.

The functional connectivity of the hippocampus with its primary cortical input, the entorhinal cortex, is organized topographically. In area CA1 of the hippocampus, this leads to different functional gradients along the proximodistal and septotemporal axes of spatial/sensory responsivity and spatial resolution respectively. CA1 ripples, a network phenomenon, allow us to test whether the hippocampal neural network shows corresponding gradients in functional connectivity along the two axes. We studied the occurrence and propagation of ripples across the entire proximodistal axis along with a comparable spatial range of the septotemporal axis of dorsal CA1. We observed that ripples could occur at any location, and their amplitudes were independent of the tetrode location along the proximodistal and septotemporal axes. When a ripple was detected on a particular tetrode ("reference tetrode"), however, the probability of cooccurrence of ripples and ripple amplitude observed on the other tetrodes decreased as a function of distance from the reference tetrode. This reduction was greater along the proximodistal axis than the septotemporal axis. Furthermore, we found that ripples propagate primarily along the proximodistal axis. Thus, over a spatial scale of ∼1.5 mm, the network is anisotropic along the two axes, complementing the topographically organized cortico-hippocampal connections.

Chrna2-OLM interneurons display different membrane properties and h-current magnitude depending on dorsoventral location.

The hippocampus is an extended structure displaying heterogeneous anatomical cell layers along its dorsoventral axis. It is known that dorsal and ventral regions show different integrity when it comes to functionality, innervation, gene expression, and pyramidal cell properties. Still, whether hippocampal interneurons exhibit different properties along the dorsoventral axis is not known. Here, we report electrophysiological properties of dorsal and ventral oriens lacunosum moleculare (OLM) cells from coronal sections of the Chrna2-cre mouse line. We found dorsal OLM cells to exhibit a significantly more depolarized resting membrane potential compared to ventral OLM cells, while action potential properties were similar between the two groups. We found ventral OLM cells to show a higher initial firing frequency in response to depolarizing current injections but also to exhibit a higher spike-frequency adaptation than dorsal OLM cells. Additionally, dorsal OLM cells displayed large membrane sags in response to negative current injections correlating with our results showing that dorsal OLM cells have more hyperpolarization-activated current (Ih ) compared to ventral OLM cells. Immunohistochemical examination indicates the h-current to correspond to hyperpolarization-activated cyclic nucleotide-gated subunit 2 (HCN2) channels. Computational studies suggest that Ih in OLM cells is essential for theta oscillations in hippocampal circuits, and here we found dorsal OLM cells to present a higher membrane resonance frequency than ventral OLM cells. Thus, our results highlight regional differences in membrane properties between dorsal and ventral OLM cells allowing this interneuron to differently participate in the generation of hippocampal theta rhythms depending on spatial location along the dorsoventral axis of the hippocampus.

Short-term dynamics of input and output of CA1 network greatly differ between the dorsal and ventral rat hippocampus.

BACKGROUND: The functional heterogeneity of the hippocampus along its longitudinal axis at the level of behavior is an established concept; however, the neurobiological mechanisms are still unknown. Diversifications in the functioning of intrinsic hippocampal circuitry including short-term dynamics of synaptic inputs and neuronal output, that are important determinants of information processing in the brain, may profoundly contribute to functional specializations along the hippocampus. The objectives of the present study were the examination of the role of the GABAA receptor-mediated inhibition, the µ-opioid receptors and the effect of stimulation intensity on the dynamics of both synaptic input and neuronal output of CA1 region in the dorsal and ventral hippocampus. We used recordings of field potentials from adult rat hippocampal slices evoked by brief repetitive activation of Schaffer collaterals. RESULTS: We find that the local CA1 circuit of the dorsal hippocampus presents a remarkably increased dynamic range of frequency-dependent short-term changes in both input and output, ranging from strong facilitation to intense depression at low and high stimulation frequencies respectively. Furthermore, the input-output relationship in the dorsal CA1 circuit is profoundly influenced by frequency and time of presynaptic activation. Strikingly, the ventral hippocampus responds mostly with depression, displaying a rather monotonous input-output relationship over frequency and time. Partial blockade of GABAA receptor-mediated transmission (by 5 µM picrotoxin) profoundly influences input and output dynamics in the dorsal hippocampus but affected only the neuronal output in the ventral hippocampus. M-opioid receptors control short-term dynamics of input and output in the dorsal hippocampus but they play no role in the ventral hippocampus. CONCLUSION: The results demonstrate that information processing by CA1 local network is highly diversified between the dorsal and ventral hippocampus. Transient detection of incoming patterns of activity and frequency-dependent sustained signaling of amplified neuronal information may be assigned to the ventral and dorsal hippocampal circuitry respectively. This disparity should have profound implications for the functional roles ascribed to distinct segments along the long axis of the hippocampus.

ß-adrenergic receptors reduce the threshold for induction and stabilization of LTP and enhance its magnitude via multiple mechanisms in the ventral but not the dorsal hippocampus.

The hippocampus is a functionally heterogeneous structure with the cognitive and emotional signal processing ascribed to the dorsal (DH) and the ventral hippocampus (VH) respectively. However, the underlying mechanisms are poorly understood. Noradrenaline is released in hippocampus during emotional arousal modulating synaptic plasticity and memory consolidation through activation of ß adrenergic receptors (ß-ARs). Using recordings of field excitatory postsynaptic potentials from the CA1 field of adult rat hippocampal slices we demonstrate that long-term potentiation (LTP) induced either by theta-burst stimulation (TBS) that mimics a physiological firing pattern of hippocampal neurons or by high-frequency stimulation is remarkably more sensitive to ß-AR activation in VH than in DH. Thus, pairing of subthreshold primed burst stimulation with activation of ß-ARs by their agonist isoproterenol (1 µM) resulted in a reliable induction of NMDA receptor-dependent LTP in the VH without affecting LTP in the DH. Activation of ß-ARs by isoproterenol during application of intense TBS increased the magnitude of LTP in both hippocampal segments but facilitated voltage-gated calcium channel-dependent LTP in VH only. Endogenous ß-AR activation contributed to the stabilization and the magnitude of LTP in VH but not DH as demonstrated by the effects of the ß-ARs antagonist propranolol (10 µM). Exogenous (but not endogenous) ß-AR activation strongly increased TBS-induced facilitation of postsynaptic excitability in VH. In DH, isoproterenol only produced a moderate and GABAergic inhibition-dependent enhancement in the facilitation of synaptic burst responses. Paired-pulse facilitation did not change with LTP at any experimental condition suggesting that expression of LTP does not involve presynaptic mechanisms. These findings suggest that ß-AR may act as a switch that selectively promotes synaptic plasticity in VH through multiple ways and provide thus a first clue to mechanisms that underlie VH involvement in emotionality.

Effects of endogenous and exogenous D1/D5 dopamine receptor activation on LTP in ventral and dorsal CA1 hippocampal synapses.

Hippocampus is importantly involved in dopamine-dependent behaviors and dopamine is a significant modulator of synaptic plasticity in the hippocampus. Moreover, the dopaminergic innervation appears to be disproportionally segregated along the hippocampal longitudinal (dorsoventral) axis with unknown consequences for synaptic plasticity. In this study we examined the actions of endogenously released dopamine and the effects of exogenous D1/D5 dopamine receptor agonists on theta-burst stimulation-induced long-term potentiation (LTP) of field excitatory synaptic potential (fEPSP) at Schaffer collateral-CA1 synapses in slices from dorsal (DH) and ventral hippocampus (VH). Furthermore, we quantified D1 receptor mRNA and protein expression levels in DH and VH. We found that blockade of D1/D5 receptors by SCH 23390 (20 µM) significantly reduced the magnitude of LTP in both DH and VH similarly suggesting that dopamine endogenously released during TBS, presumably mimicking low activity of DA neurons, exerts a homogeneous modulation of LTP along the hippocampal long axis. Moderate to high concentrations of the selective partial D1/D5 receptor agonist SKF 38393 (50-150 µM) did not significantly change LTP in either hippocampal segment. However, the full D1 receptor selective agonist SKF 82958 (10 µM) significantly enhanced LTP in VH but not DH. Furthermore, the expression of D1 receptor mRNA and protein was considerably higher in VH compared with DH. These results suggest that the dynamic range of D1/D5 receptor-mediated dopamine effects on LTP may be higher in VH than DH and that VH may be specialized to acquire information about behaviorally relevant strong stimuli signaled by the dopamine system.

Gradient COUP-TFI Expression Is Required for Functional Organization of the Hippocampal Septo-Temporal Longitudinal Axis.

The hippocampus (HP), a medial cortical structure, is subdivided into a distinct dorsal (septal) and ventral (temporal) portion, which is separated by an intermediate region lying on a longitudinal curvature. While the dorsal portion is more dedicated to spatial navigation and memory, the most ventral part processes emotional information. Genetic factors expressed in gradient during development seem to control the size and correct positioning of the HP along its longitudinal axis; however, their roles in regulating differential growth and in supporting its anatomical and functional dissociation remain unexplored. Here, we challenge the in vivo function of the nuclear receptor COUP-TFI (chicken ovalbumin upstream promoter transcription factor 1) in controlling the hippocampal, anatomical, and functional properties along its longitudinal axis. Loss of cortical COUP-TFI function results in a dysmorphic HP with altered shape, volume, and connectivity, particularly in its dorsal and intermediate regions. Notably, topographic inputs from the entorhinal cortex are strongly impaired in the dorsal portion of COUP-TFI mutants. These severe morphological changes are associated with selective spatial learning and memory impairment. These findings identify a novel transcriptional regulator required in the functional organization along the hippocampal septo-temporal axis supporting a genetic basis of the hippocampal volumetric growth with its final shape, circuit, and type of memory function.

A gradient of frequency-dependent synaptic properties along the longitudinal hippocampal axis.

BACKGROUND: The hippocampus is a functionally heterogeneous brain structure and specializations of the intrinsic neuronal network may crucially support the functional segregation along the longitudinal axis of the hippocampus. Short-term synaptic plasticity plays fundamental roles in information processing and may be importantly involved in diversifying the properties of local neuronal network along the hippocampus long axis. Therefore, we aimed to examine the properties of the cornu ammonis 1 (CA1) synapses along the entire dorsoventral axis of the rat hippocampus using field excitatory postsynaptic potentials from transverse rat hippocampal slices and a frequency stimulation paradigm. RESULTS: Applying a ten-pulse stimulus train at frequencies from 0.1 to 100 Hz to the Schaffer collaterals we found a gradually diversified pattern of frequency-dependent synaptic effects along the dorsoventral hippocampus axis. The first conditioned response was facilitated along the whole hippocampus for stimulus frequencies 10-40 Hz. However, steady-state responses or averaged responses generally ranged from maximum synaptic facilitation in the most dorsal segment of the hippocampus to maximum synaptic depression in the most ventral segment of the hippocampus. In particular, dorsal synapses facilitated for stimulus frequency up to 50 Hz while they depressed at higher frequencies (75-100 Hz). Facilitation at dorsal synapses was maximal at stimulus frequency of 20 Hz. On the contrary, the most ventral synapses showed depression regardless of the stimulus frequency, only displaying a transient facilitation at the beginning of 10-50 Hz stimulation. Importantly, the synapses in the medial hippocampus displayed a transitory behavior. Finally, as a whole the hippocampal synapses maximally facilitated at 20 Hz and increasingly depressed at 50-100 Hz. CONCLUSION: The short-term synaptic dynamics change gradually along the hippocampal long axis in a frequency-dependent fashion conveying distinct properties of information processing to successive segments of the structure, thereby crucially supporting functional segregation along the dorsoventral axis of the hippocampus.

The Avian Hippocampal Formation and the Stress Response.

Though widely studied for its function in memory and navigation, the hippocampal formation (HF) in mammals also plays an important role in regulating the stress response. If this is an ancestral feature of the hippocampus, then it is likely that the avian HF plays a similar role. Indeed, the avian HF strongly expresses both mineralocorticoid and glucocorticoid receptors, and has indirect projections to the paraventricular nucleus of the hypothalamus, which controls the hypothalamic-pituitary-adrenal (HPA) axis. Hippocampal lesions increase HPA activity, while electrical stimulation suppresses it. In addition, adult hippocampal neurogenesis in birds is reduced in response to different acute and chronic stressors, as it is in mammals. Because the mammalian hippocampus is functionally specialized along its septotemporal axis, with the temporal pole playing a more important role in the stress response, the hypothesis is put forward that a similar functional specialization exists in birds along the rostrocaudal hippocampal axis. Some, though not all, of the evidence supports a rostrocaudal functional gradient. The evidence for whether this is equivalent to the mammalian septotemporal organization is currently ambiguous at best and needs to be more extensively investigated.

Neurogenesis in the septal and temporal part of the adult rat dentate gyrus.

Structural and functional dissociation between the septal and the temporal part of the dentate gyrus predispose for possible differentiations in the ongoing neurogenesis process of the adult hippocampus. In this study, BrdU-dated subpopulations of the rat septal and temporal dentate gyrus (coexpressing GFAP, DCX, NeuN, calretinin, calbindin, S100, caspase-3 or fractin) were quantified comparatively at 2, 5, 7, 14, 21, and 30 days after BrdU administration in order to examine the successive time-frames of the neurogenesis process, the glial or neuronal commitment of newborn cells and the occurring apoptotic cell death. Newborn neurons' migration from the neurogenic subgranular zone to the inner granular cell layer and expression of glutamate NMDA and AMPA receptors were also studied. BrdU immunocytochemistry revealed comparatively higher numbers of BrdU(+) cells in the septal part, but stereological analysis of newborn and total granule cells showed an identical ratio in the two parts, indicating an equivalent neurogenic ability, and a common topographical pattern along each part's longitudinal and transverse axis. Similarly, both parts exhibited extremely low levels of newborn glial and apoptotic cells. However, despite the initially equal division rate and pattern of the septal and temporal proliferating cells, their later proliferative profile diverged in the two parts. Dynamic differences in the differentiation, migration and maturation process of the two BrdU-incorporating subpopulations of newborn neurons were also detected, along with differences in their survival pattern. Therefore, we propose that various factors, including developmental date birth, local DG microenvironment and distinct functionality of the two parts may be the critical regulators of the ongoing neurogenesis process, leading the septal part to a continuous, rapid, and less-disciplined genesis rate, whereas the quiescent temporal microenvironment preserves a quite steady, less-demanding neurogenesis process.

Selection for tameness, a key behavioral trait of domestication, increases adult hippocampal neurogenesis in foxes.

Work on laboratory and wild rodents suggests that domestication may impact on the extent of adult hippocampal neurogenesis and its responsiveness to regulatory factors. There is, however, no model of laboratory rodents and their nondomesticated conspecifics that would allow a controlled comparison of the effect of domestication. Here, we present a controlled within-species comparison of adult hippocampal neurogenesis in farm-bred foxes (Vulpes vulpes) that differ in their genetically determined degree of tameness. Quantitative comparisons of cell proliferation (Ki67) and differentiating cells of neuronal lineage (doublecortin, DCX) in the hippocampus of foxes were performed as a proxy for neurogenesis. Higher neurogenesis was observed in tameness-selected foxes, notably in an extended subgranular zone of the middle and temporal compartments of the hippocampus. Increased neurogenesis is negatively associated with aggressive behavior. Across all animals, strong septotemporal gradients were found, with higher numbers of proliferating cells and young neurons relative to resident granule cells in the temporal than in the septal hippocampus. The opposite gradient was found for the ratio of DCX/Ki67- positive cells. When tameness-selected and unselected foxes are compared with rodents and primates, proliferation is similar, while the number of young neurons is higher. The difference may be mediated by an extended period of differentiation or higher rate of survival. On the background of this species-specific neurogenic pattern, selection of foxes for a single behavioral trait key to domestication, i.e., genetic tameness, is accompanied by global and region-specific increases in neurogenesis.

The α5GABAA receptor modulates the induction of long-term potentiation at ventral but not dorsal CA1 hippocampal synapses.

The hippocampal synapses display conspicuous ability for long-term plasticity which is thought to underlie learning and memory. Growing evidence shows that this ability differs along the long axis of the hippocampus, with the ventral CA1 hippocampal synapses displaying remarkably lower ability for long-term potentiation (LTP) compared with their dorsal counterpart when activated with high-frequency stimulation. Here, we show that low frequency, 10 Hz stimulation induced LTP more reliably in dorsal than in ventral CA1 field. Blockade of alpha5 subunit-containing GABAA receptors eliminated the difference between dorsal and ventral hippocampus. We propose that α5GABAA receptor-mediated activity plays a crucial role in regulating the threshold for induction of LTP especially at the ventral CA1 hippocampal synapses. This might have important implications for the functional specialization along the hippocampus.

Luteolin promotes neuronogenesis in hippocampus of chronic unpredictable mild stress rats and primary hippocampus of fetal rats.

OBJECTIVE: To investigate the effects of luteolin on chronic unpredictable mild stress (CUMS)-induced depressive rats and corticosterone (CORT)-induced depressive primary hippocampal neurons, and to elucidate the mechanism behind the action. METHODS: The antidepressant mechanism of luteolin was studied by using CUMS rat model and primary hippocampal neurons in fetal rats. In vivo, novelty suppressed feeding, open-field and sucrose preference tests as well as Morris water maze were evaluated. The content of brain derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in serum were detected by enzyme-linked immunosorbent assay. The mechanisms of luteolin were explored based on neurotrophin and hippocampal neurogenesis, and proliferation. Survival of the septo-temporal axis in hippocampus was assayed using the 5-bromo-2-deoxyuridine (BrdU), the expression of BDNF, neurotrophin-3 (NT-3), and nerve growth factor (NGF) in hippocampus dentate gyrus region were measured by Western-blotting. In vitro, BDNF, NT-3, tropomyosin receptor kinase B (TrkB), and phosphorylated cyclic adenosine monophosphate responsive element binding protein (p-CREB) were detected through the high content analysis (HCA) to investigate neurotrophin and apoptosis. RESULTS: Induction of CUMS in rats induced depressive symptoms, while luteolin significantly enhanced sucrose consumption, decreased feeding latency, increased locomotor activity, escape latency, distance of target quadrant and regulated the content of depressive-like biomarkers. Histology analysis revealed that luteolin increased the abundance of new born neurons that had been labeled with BrdU, BrdU + neuronal nuclear antigen, and BrdU + doublecortin in septo-temporal axis of S2 (mid-septal) and T3 (mid-temporal). Moreover, expression of BDNF, NT-3, and NGF increased significantly in the septo-temporal axis of S2 and T3. HCA showed increased expression of BDNF, NT-3, TrkB and p-CREB in primary hippocampal neurons. CONCLUSION: The results provided direct evidence that luteolin has an antidepressant effect and could effectively promote the regeneration of the septotemporal axis nerve and hippocampal neuronutrition, which suggested that the antidepressant effect of luteolin may be related to hippocampal neurogenesis.

Differential functions of the dorsal and intermediate regions of the hippocampus for optimal goal-directed navigation in VR space.

Goal-directed navigation requires the hippocampus to process spatial information in a value-dependent manner, but its underlying mechanism needs to be better understood. Here, we investigated whether the dorsal (dHP) and intermediate (iHP) regions of the hippocampus differentially function in processing place and its associated value information. Rats were trained in a place-preference task involving reward zones with different values in a visually rich virtual reality environment where two-dimensional navigation was possible. Rats learned to use distal visual scenes effectively to navigate to the reward zone associated with a higher reward. Inactivation of both dHP and iHP with muscimol altered the efficiency and precision of wayfinding behavior, but iHP inactivation induced more severe damage, including impaired place preference. Our findings suggest that the iHP is more critical for value-dependent navigation toward higher-value goal locations.

Region-dependent and stage-specific effects of stress, environmental enrichment, and antidepressant treatment on hippocampal neurogenesis.

Chronic stress and depression are associated with decreased levels of hippocampal neurogenesis. On the other hand, antidepressants as well as environmental enrichment may rely in part on their pro-neurogenic effects to improve cognition and mood. Because a functional heterogeneity has been consistently reported along the septo-temporal axis of the hippocampus, regional changes in neurogenesis could differentially contribute to these effects and affect distinct hippocampal functions. Mapping these regional changes could therefore provide a better understanding of the function of newborn neurons. While some studies report region-specific effects of stress and antidepressants on neurogenesis, it is unclear whether these changes affect distinct populations of newborn neurons according to their developmental stage in a region-specific manner. By using endogenous markers and BrdU labeling we quantified the regional changes in cell proliferation and survival as well as in the number of neuronal progenitors and immature neurons following unpredictable chronic mild stress (UCMS), environmental enrichment (EE) and chronic fluoxetine (20 mg/kg/day) treatment along the septo-temporal axis of the hippocampus. EE promoted cell proliferation and survival of 4-week-old newborn cells as well as increased the number and proportion of post-mitotic immature neurons specifically within the septal hippocampus. By contrast, UCMS uniformly decreased cell proliferation, survival and immature newborn neurons but differentially affected progenitor cells with a decrease restricted to the temporal regions of the hippocampus. Whereas fluoxetine treatment in control mice affected proliferation and survival specifically in the temporal hippocampus, it reversed most of the UCMS-induced alterations all along the septo-temporal axis. These results highlight that different factors known for exerting a mood improving effect differentially regulate neurogenesis along the septo-temporal axis of the hippocampus. Such region and stage specific effects may correlate to distinct functional properties of newborn neurons along the septo-temporal axis of the hippocampus which may contribute differently to the pathophysiology of affective disorders.

Increased Inhibition May Contribute to Maintaining Normal Network Function in the Ventral Hippocampus of a Fmr1-Targeted Transgenic Rat Model of Fragile X Syndrome.

A common neurobiological mechanism in several neurodevelopmental disorders, including fragile X syndrome (FXS), is alterations in the balance between excitation and inhibition in the brain. It is thought that in the hippocampus, as in other brain regions, FXS is associated with increased excitability and reduced inhibition. However, it is still not known whether these changes apply to both the dorsal and ventral hippocampus, which appear to be differently involved in neurodegenerative disorders. Using a Fmr1 knock-out (KO) rat model of FXS, we found increased neuronal excitability in both the dorsal and ventral KO hippocampus and increased excitatory synaptic transmission in the dorsal hippocampus. Interestingly, synaptic inhibition is significantly increased in the ventral but not the dorsal KO hippocampus. Furthermore, the ventral KO hippocampus displays increased expression of the α1GABAA receptor subtype and a remarkably reduced rate of epileptiform discharges induced by magnesium-free medium. In contrast, the dorsal KO hippocampus displays an increased rate of epileptiform discharges and similar expression of α1GABAA receptors compared with the dorsal WT hippocampus. Blockade of α5GABAA receptors by L-655,708 did not affect epileptiform discharges in any genotype or hippocampal segment, and the expression of α5GABAA receptors did not differ between WT and KO hippocampus. These results suggest that the increased excitability of the dorsal KO hippocampus contributes to its heightened tendency to epileptiform discharges, while the increased phasic inhibition in the Fmr1-KO ventral hippocampus may represent a homeostatic mechanism that compensates for the increased excitability reducing its vulnerability to epileptic activity.

Septotemporal variation in modulation of synaptic transmission, paired-pulse ratio and frequency facilitation/depression by adenosine and GABAB receptors in the rat hippocampus.

Short-term synaptic plasticity represents a fundamental mechanism in neural information processing and is regulated by neuromodulators. Here, using field recordings from the CA1 region of adult rat hippocampal slices, we show that excitatory synaptic transmission is suppressed by strong but not moderate activation of adenosine A1 receptors by 2-Chloro-N6-cyclopentyladenosine (CCPA) more in the dorsal than the ventral hippocampus; in contrast, both mild and strong activation of GABAB receptors by baclofen (1 µM, 10 µM) suppress synaptic transmission more in the ventral than the dorsal hippocampus. Using a 10-pulse stimulation train of variable frequency, we found that CCPA modulates short-term synaptic plasticity independently of the suppression of synaptic transmission in both segments of the hippocampus and at stimulation frequencies greater than 10 Hz. However, specifically regarding the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D) we found significant drug action before but not after adjusting conditioning responses to control levels. Activation of GABABRs by baclofen suppressed synaptic transmission more in the ventral than the dorsal hippocampus. Furthermore, relatively high (10 µM) but not low (1 µM) baclofen concentration enhanced both PPR and FF in both hippocampal segments at stimulation frequencies greater than 1 Hz, independently of the suppression of synaptic transmission by baclofen. These results show that A1Rs and GABABRs control synaptic transmission more effectively in the dorsal and the ventral hippocampus, respectively, and suggest that these receptors modulate PPR and FF/D at different frequency bands of afferent input, in both segments of the hippocampus.