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PubMed1996

The alvear pathway of the rat hippocampus.

Neurons of the entorhinal cortex project to the hippocampus proper and dentate gyrus. This projection is called the "perforant pathway" because it perforates the subiculum; current usage applies this term to all entorhino-hippocampal fibers. However, entorhinal fibers also reach Ammon's horn via the alveus ("alvear pathway"), an alternative route first described by Cajal. The anterograde tracer Phaseolus vulgaris leucoagglutinin (PHAL) was used in order to analyze the contribution of this pathway to the temporo-ammonic projection. In the temporal portion of the rat hippocampus, most of the entorhinal fibers reach Ammon's horn after perforating the subiculum (classical perforant pathway). At more septal levels, the number of entorhinal fibers that take the alvear pathway increases; in the septal portion of the hippocampal formation, most of the entorhinal fibers to hippocampal subfield CA1 reach this subfield via the alveus. These fibers make sharp right-angle turns in the alveus, perforate the pyramidal cell layer, and finally terminate in the stratum lacunosum-moleculare. The crossed temporo-ammonic fibers reach their termination area in the stratum lacunosum-moleculare of CA1 almost exclusively via the alveus. These data indicate that the alveus is a major route by which entorhinal fibers reach their targets in CA1.

Animals↗
PubMed2005

Differentiability of simulated MEG hippocampal, medial temporal and neocortical temporal epileptic spike activity.

Previous studies have shown that magnetoencephalography (MEG) can measure hippocampal activity, despite the cylindrical shape and deep location in the brain. The current study extended this work by examining the ability to differentiate the hippocampal subfields, parahippocampal cortex, and neocortical temporal sources using simulated interictal epileptic activity. A model of the hippocampus was generated on the MRIs of five subjects. CA1, CA3, and dentate gyrus of the hippocampus were activated as well as entorhinal cortex, presubiculum, and neocortical temporal cortex. In addition, pairs of sources were activated sequentially to emulate various hypotheses of mesial temporal lobe seizure generation. The simulated MEG activity was added to real background brain activity from the five subjects and modeled using a multidipole spatiotemporal modeling technique. The waveforms and source locations/orientations for hippocampal and parahippocampal sources were differentiable from neocortical temporal sources. In addition, hippocampal and parahippocampal sources were differentiated to varying degrees depending on source. The sequential activation of hippocampal and parahippocampal sources was adequately modeled by a single source; however, these sources were not resolvable when they overlapped in time. These results suggest that MEG has the sensitivity to distinguish parahippocampal and hippocampal spike generators in mesial temporal lobe epilepsy.

Entorhinal Cortex↗
PubMed1994

Distribution of nicotinic receptors in the human hippocampus and thalamus.

Neuronal nicotinic acetylcholine receptors consist of different subunits, alpha and beta, with different subtype arrangement corresponding to distinct pharmacological and functional properties. The expression of alpha 3, alpha 7 and beta 2 mRNA in the human brain was studied by in situ hybridization and compared to [3H]nicotine, [3H]cytisine and [125I]alpha-bungarotoxin binding in contiguous sections. The beta 2 probe showed a strong hybridization signal in the granular layer of the dentate gyrus and in the CA2/CA3 region of the hippocampus and in the insular cortex, and a signal of lower intensity in the subicular complex and entorhinal cortex. The alpha 3 probe showed strong hybridization in the dorsomedial, lateral posterior, ventroposteromedial and reticular nuclei of the thalamus, and a weak signal in the hippocampal region and in the entorhinal, insular and cingular cortex. The amount of alpha 7 mRNA was high at the level of the dentate granular layer and the CA2/CA3 region of the hippocampus, in the caudate nucleus and in the pulvinar and ventroposterolateral nuclei of the thalamus. [3H]Nicotine and [3H]cytisine binding appeared to be identical in anatomical distribution and relative intensity. It was high in the thalamic nuclei, the putamen and in the hippocampal formation in the subicular complex and the stratum lacunosum moleculare. The level of [125I]alpha-bungarotoxin binding was particularly high in the hippocampus and in the pyramidal cells of the CA1 region, but was relatively low in the subicular complex. Our data indicate that in the human brain nicotinic receptor subtypes have discrete distributions, which are in part different from those of other species.

Adult↗
PubMed2006

From grid cells to place cells: a mathematical model.

Anatomical connectivity and recent neurophysiological results imply that grid cells in the medial entorhinal cortex are the principal cortical inputs to place cells in the hippocampus. The authors propose a model in which place fields of hippocampal pyramidal cells are formed by linear summation of appropriately weighted inputs from entorhinal grid cells. Single confined place fields could be formed by summing input from a modest number (10-50) of grid cells with relatively similar grid phases, diverse grid orientations, and a biologically plausible range of grid spacings. When the spatial phase variation in the grid-cell input was higher, multiple, and irregularly spaced firing fields were formed. These observations point to a number of possible constraints in the organization of functional connections between grid cells and place cells.

Animals↗
PubMed2001

Borders and cytoarchitecture of the perirhinal and postrhinal cortices in the rat.

Cytoarchitectonic and histochemical analyses were carried out for perirhinal areas 35 and 36 and the postrhinal cortex, providing the first detailed cytoarchitectonic study of these regions in the rat brain. The rostral perirhinal border with insular cortex is at the extreme caudal limit of the claustrum, consistent with classical definitions of insular cortex dating back to Rose ([1928] J. Psychol. Neurol. 37:467-624). The border between the perirhinal and postrhinal cortices is at the caudal limit of the angular bundle, as previously proposed by Burwell et al. ([1995] Hippocampus 5:390-408). The ventral borders with entorhinal cortex are consistent with the Insausti et al. ([1997] Hippocampus 7:146-183) description of that region and the Dolorfo and Amaral ([1998] J. Comp. Neurol. 398:25-48) connectional findings. Regarding the remaining borders, both the perirhinal and postrhinal cortices encroach upon temporal cortical regions as defined by others (e.g., Zilles [1990] The cerebral cortex of the rat, p 77-112; Paxinos and Watson [1998] The rat brain in stereotaxic coordinates). Based on cytoarchitectonic and histochemical criteria, perirhinal areas 35 and 36 and the postrhinal cortex were further subdivided. Area 36 was parceled into three subregions, areas 36d, 36v, and 36p. Area 35 was parceled into two cytoarchitectonically distinctive subregions, areas 35d and 35v. The postrhinal cortex was divided into two subregions, areas PORd and PORv. These regional definitions of perirhinal areas 35 and 36 and the postrhinal cortex were confirmed by new empirical analyses of previously reported quantitative connectional data (Burwell and Amaral [1998a] J. Comp. Neurol. 398:179-205).

Acetylcholinesterase↗
PubMed2004

DNA targeting of rhinal cortex D2 receptor protein reversibly blocks learning of cues that predict reward.

When schedules of several operant trials must be successfully completed to obtain a reward, monkeys quickly learn to adjust their behavioral performance by using visual cues that signal how many trials have been completed and how many remain in the current schedule. Bilateral rhinal (perirhinal and entorhinal) cortex ablations irreversibly prevent this learning. Here, we apply a recombinant DNA technique to investigate the role of dopamine D2 receptor in rhinal cortex for this type of learning. Rhinal cortex was injected with a DNA construct that significantly decreased D2 receptor ligand binding and temporarily produced the same profound learning deficit seen after ablation. However, unlike after ablation, the D2 receptor-targeted, DNA-treated monkeys recovered cue-related learning after 11-19 weeks. Injecting a DNA construct that decreased N-methyl-d-aspartate but not D2 receptor ligand binding did not interfere with learning associations between the cues and the schedules. A second D2 receptor-targeted DNA treatment administered after either recovery from a first D2 receptor-targeted DNA treatment (one monkey), after N-methyl-d-aspartate receptor-targeted DNA treatment (two monkeys), or after a vector control treatment (one monkey) also induced a learning deficit of similar duration. These results suggest that the D2 receptor in primate rhinal cortex is essential for learning to relate the visual cues to the schedules. The specificity of the receptor manipulation reported here suggests that this approach could be generalized in this or other brain pathways to relate molecular mechanisms to cognitive functions.

Animals↗
PubMed1996

Regeneration of entorhino-dentate projections in organotypic slice cultures: mode of axonal regrowth and effects of growth factors.

Explants of Embryonic Day 18 (E18) rat entorhinal cortex were cocultured with Postnatal Day 6 mouse hippocampal slices to study CNS regeneration in vitro. The present report describes a double-labeling paradigm for quantitative analysis of the type of new growth seen in immature cultures. Entorhinal projection neurons in living static cocultures were retrogradely labeled with DiI or Texas red-dextran at 6 days in vitro and with dextran-FITC at 13 days. An intervening lesion to the entorhinodentate pathway was made at 8 days by replacing the hippocampal slices with fresh ones. About one-third of the new efferent entorhinal projections labeled with the second tracer could be characterized as true regeneration of axons from previously projecting entorhinal neurons by virtue of their being double labeled. The remaining two-thirds comprised new, late-arriving axons from previously nonprojecting cells. Earlier studies have shown that rat entorhinal axons will reinnervate hippocampal slices only if the lesions are made before 2-3 weeks in culture, equivalent to a postnatal age of 11-18 days. In a second series of experiments we tested whether treatment with trophic factors could overcome this age-related failure of regeneration characteristic of mature preparations. E18 explants were lesioned after 4 weeks in vitro and grown for a further 2 weeks in medium supplemented with either Schwann cell conditioned medium or acidic fibroblast growth factor plus heparin. A significant increase in outgrowth was seen in both cases, although the effects of each factor were not additive when they were applied in combination. These results show that our model of CNS lesions in vitro can be used to assess the effectiveness of growth factors in ameliorating the decline in regenerative ability with increasing developmental age.

Animals↗
PubMed1996

Afferents to the seizure-sensitive neurons in layer III of the medial entorhinal area: a tracing study in the rat.

Neurons in layer III of the medial entorhinal area (MEA) in the rat are extremely vulnerable to local injections of amino-oxyacetic acid and to experimentally induced limbic seizures. A comparable specific pathology has been noted in surgical specimens from patients with temporal lobe epilepsy. Efforts to understand this preferential neuronal vulnerability led us to study the neural input to this layer in the rat. Iontophoretic injection of the retrograde tracer fast blue, aimed at layer III of the MEA, resulted in retrogradely labeled neurons in the presubiculum in all the injected hemispheres. The nucleus reuniens thalami, the anteromedial thalamic nucleus, the ventral portion of the claustrum (endopiriform nucleus), the dorsomedial parts of the anteroventral thalamic nucleus, and the septum-diagonal band complex were labeled less frequently. In only one experiment, retrogradely labeled neurons were observed in the ventrolateral hypothalamus and in the brainstem nucleus raphe dorsalis. Since projections from claustrum to the entorhinal cortex has not been studied in the rat with modern sensitive anterograde tracing techniques, iontophoretic injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin were placed into the ventral portion of the claustrum. Anterogradely labeled fibers in the entorhinal area proved not to be confined to the MEA, since a prominent projection distributed to the lateral entorhinal area as well. In both areas, the densest terminal labeling was present in layers IV-VI, whereas layer III appeared to be only sparsely labeled. The present data indicate that of all potential afferents only those from the presubiculum distribute preferentially to layer III of the MEA. This, in turn, suggests a potentially important role of the presubiculum in the seizure-related degeneration of neurons in layer III of the MEA.

Afferent Pathways↗
PubMed1999

Ovariectomy of adult rats leads to increased expression of astrocytic basic fibroblast growth factor in the ventral tegmental area and in dopaminergic projection regions of the entorhinal and prefrontal cortex.

Changes in astrocytic function may underlie the neurochemical and morphological alterations in limbic and cortical areas after estrogen loss in adult females. We assessed whether increased expression of basic fibroblast growth factor (bFGF), an astrocytic response involved in injury-induced neuronal plasticity, occurs after ovariectomy. We examined bFGF immunoreactivity (IR) in ovariectomized rats with oil or estradiol benzoate (5 microgram every 4 d; Experiment 1) and in ovariectomized and intact animals (Experiment 2). In the ventral tegmental area (VTA), bFGF-IR and glial fibrillary acidic protein (GFAP)-IR were greater in ovariectomized animals than in animals with estrogen replacement. bFGF-IR in the VTA was greater in ovariectomized than in intact females. In the dorsal raphe, no differences between groups were found in GFAP-IR or bFGF-IR. In mesolimbic dopaminergic target areas within entorhinal cortex (Ent), prefrontal cortex, and nucleus accumbens, bFGF-IR was higher in Ent of ovariectomized animals 4 weeks after surgery in both experiments, but no differences were seen in nucleus accumbens or in an occipital cortical, control, area in either study. In Experiment 2, small increases in bFGF-IR were seen in the prefrontal cortex after ovariectomy. In the VTA and Ent, changes in bFGF-IR developed gradually, peaking at 4 weeks and waning at 40 weeks. Furthermore, increased dendritic arbor of Ent layer II/III pyramidal cells was found in ovariectomized females with the use of a modified Golgi-Cox staining procedure. These findings suggest that, within specific regions, ovariectomy induces astrocytic responses similar to those observed after injury that may affect neuronal chemistry and morphology.

Animals↗
PubMed2003

AMPA/kainate and group-I metabotropic receptor antagonists infused into different brain areas impair memory formation of inhibitory avoidance in rats.

Several lines of evidence suggest that glutamate receptors are involved in memory processing. To examine the role of non-N-methyl-D-aspartate (non-NMDA) glutamate receptors on memory consolidation, rats were bilaterally implanted with cannulae aimed at the CA1 region of the dorsal hippocampus (CA1), entorhinal cortex (ENTO), posterior parietal cortex (PPC) or the basolateral nucleus of the amygdala (BLA), and trained in a one-trial step-down inhibitory avoidance task. At different times after training, the alpha-amino 3-hydroxy-5 methyl 4-isoxazole propionate (AMPA) receptor blocker, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (1.0 microg/side), or the metabotropic type-I receptor antagonist, 2-amino-3-phosphonopropionic acid (AP3) (1.0 microg/side), were infused into the above-mentioned structures. CNQX produced retrograde amnesia when infused into BLA or CA1 0, 30, 90 or 180 min post-training but not at later times. AP3 blocked memory consolidation when administered into CA1 0, 30 or 180 min post-training, while in BLA, it was amnestic only when given 0 or 30 min after the training session. CNQX and AP3 had no effect on memory when administered into ENTO or PPC at any time. Our data suggest that the consolidation of the avoidance memory requires intact non-NMDA receptor function in the hippocampus and the basolateral nucleus of the amygdala, but not necessarily in the entorhinal and parietal cortex, for long periods after training.

Amygdala↗
PubMed2004

MRI-derived entorhinal volume is a good predictor of conversion from MCI to AD.

With high-resolution quantitative magnetic resonance imaging (MRI) techniques, it is possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer's disease (AD). In the present study, 27 patients diagnosed with mild cognitive impairment (MCI) received a high-resolution MRI scan at baseline and were followed with yearly clinical evaluations. Ten of the 27 patients converted to AD during a 36-month period following the baseline clinical evaluation. Hippocampal and entorhinal cortex volumes derived from the baseline scan were compared to determine which of these two regions, known to be pathologically involved very early in the course of AD, could best differentiate MCI converters from non-converters. Although both entorhinal and hippocampal volumes were found to be independent predictors of the likelihood of conversion to AD, it was the right hemisphere entorhinal volume that best predicted conversion with a concordance rate of 93.5%.

Aged↗
PubMed2005

Neurogliaform neurons form a novel inhibitory network in the hippocampal CA1 area.

We studied neurogliaform neurons in the stratum lacunosum moleculare of the CA1 hippocampal area. These interneurons have short stellate dendrites and an extensive axonal arbor mainly located in the stratum lacunosum moleculare. Single-cell reverse transcription-PCR showed that these neurons were GABAergic and that the majority expressed mRNA for neuropeptide Y. Most neurogliaform neurons tested were immunoreactive for alpha-actinin-2, and many stratum lacunosum moleculare interneurons coexpressed alpha-actinin-2 and neuropeptide Y. Neurogliaform neurons received monosynaptic, DNQX-sensitive excitatory input from the perforant path, and 40 Hz stimulation of this input evoked EPSCs displaying either depression or initial facilitation, followed by depression. Paired recordings performed between neurogliaform neurons showed that 85% of pairs were electrically connected and 70% were also connected via GABAergic synapses. Injection of sine waveforms into neurons during paired recordings resulted in transmission of the waveforms through the electrical synapse. Unitary IPSCs recorded from neurogliaform pairs readily fatigued, had a slow decay, and had a strong depression of the synaptic response at a 5 Hz stimulation frequency that was antagonized by the GABA(B) antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl) phosphinic acid (CGP55845). The amplitude of the first IPSC during the 5 Hz stimulation was also increased by CGP55845, suggesting a tonic inhibition of synaptic transmission. A small unitary GABA(B)-mediated IPSC could also be detected, providing the first evidence for such a component between GABAergic interneurons. Electron microscopic localization of the GABA(B1) subunit at neurogliaform synapses revealed the protein in both presynaptic and postsynaptic membranes. Our data disclose a novel interneuronal network well suited for modulating the flow of information between the entorhinal cortex and CA1 hippocampus.

Animals↗
PubMed1997

Neurons and extracellular neurofibrillary tangles in the hippocampal subdivisions in early-onset familial Alzheimer's disease: a case study.

We have investigated morphometrically unaffected neurons, intracellular neurofibrillary tangles (I-NFT) and extracellular neurofibrillary tangles (E-NFT) in eight subdivisions of the hippocampal cortex in two cases of early-onset familial Alzheimer's disease (FAD) and six cases of early-onset sporadic Alzheimer's disease (SAD). The hippocampal subdivisions examined included: CA4, CA3, CA2, CA1, prosubiculum, subiculum and presubiculum (PRE), parasubiculum (PARA) and entorhinal cortex (ENT). CA3, CA2 and CA1 in the FAD cases showed more severe neuronal loss and much greater E-NFT formation than in the SAD cases, while ENT in both the FAD cases showed less neuronal loss and less E-NFT formation. These data suggest that the cornu ammonis is affected more severely than the ENT in the FAD cases. These observations indicate that hippocampal pathology in the FAD cases is qualitatively as well as quantitatively different from that in sporadic cases. These results provide further evidence for pathological heterogeneity in AD, although the number of FAD cases examined is very small.

Aged↗
PubMed2004

Discrimination of social odors and their locations: role of lateral entorhinal area.

Discrimination of individual conspecifics by their odors has been reported for many mammalian species, but little information is available on the brain mechanisms underlying such discrimination. A previous study reported that large parahippocampal lesions, centered on entorhinal cortex but extending into adjacent areas of the brain, eliminated female hamsters' ability to discriminate the flank gland odors of different individuals, as tested with habituation-dishabituation methods. The current study examined the effects of lesions restricted to the lateral entorhinal area on such discriminations. Female hamsters were tested in several types of habituation procedure that differed across a sequence of trials in the locations of familiar and novel social odors. Discrimination of two individuals' odors depended on the sequences of locations of the odors, indicating that odor identity and location were simultaneously salient to female hamsters. Lesions of lateral entorhinal area interfered with this spatial-olfactory discrimination. When confounding spatial cues were eliminated, hamsters did discriminate between novel and familiar odors, and lesions in the entorhinal area did not eliminate this ability. Thus, although the lateral entorhinal area is not necessary for individual odor discrimination, it is involved in processing odor-place combinations.

Animals↗
PubMed1997

The effect of combined fluid percussion and entorhinal cortical lesions on long-term potentiation.

Among the pathological processes initiated by traumatic brain injury are excessive neuroexcitation and target cell deafferentation. The current study examines the contribution of these injury components, separately as well as their combined effect, on postinjury alterations in the capacity for long-term potentiation and the immunolocalization of N-methyl-D-aspartate receptors and GABA. Adult rats underwent central fluid percussion traumatic brain injury, electrolytic bilateral entorhinal cortex lesions, or a combined injury of both procedures separated by 24 h. At two or 15 days postinjury, the capacity for long-term potentiation of the Schaffer collateral-commissural input to CA1 was measured in acute electrophysiological recordings. Entorhinal cortical lesions resulted in time-dependent increases in the effectiveness of tetanic stimulation to elevate population postsynaptic potentials and population spike amplitudes. These lesions also resulted in a marked intensification in the density of N-methyl-D-aspartate receptors in the CA1 stratum lacunosum-moleculare. All injury conditions that included fluid percussion as a component (alone or in combined injuries) produced a persistent impairment in long-term potentiation of the evoked population postsynaptic potentials. Thus, in combined injuries, the presence of concussion-induced neuroexcitation attenuated deafferentation-induced response increases. Both N-methyl-D-aspartate receptor and GABA immunobinding following combined injuries were also reduced relative to those observed following entorhinal lesions alone. The present results suggest that a process of receptor plasticity, possibly involving reactive synaptogenesis, may contribute to postdeafferentation enhancements of long-term potentiation, and that a traumatic brain insult will attenuate these enhancements. This interaction of different injury components suggests that recovery of function following brain injury may be enhanced by pharmacological reduction of neuroexcitation during postinjury intervals of reactive receptor plasticity.

Animals↗
PubMed2003

Medial temporal lobe atrophy in patients with refractory temporal lobe epilepsy.

OBJECTIVE: The objective of this study was to assess the volumes of medial temporal lobe structures using high resolution magnetic resonance images from patients with chronic refractory medial temporal lobe epilepsy (MTLE). METHODS: We studied 30 healthy subjects, and 25 patients with drug refractory MTLE and unilateral hippocampal atrophy (HA). We used T1 magnetic resonance images with 1 mm isotropic voxels, and applied a field non-homogeneity correction and a linear stereotaxic transformation into a standard space. The structures of interest are the entorhinal cortex, perirhinal cortex, parahippocampal cortex, temporopolar cortex, hippocampus, and amygdala. Structures were identified by visual examination of the coronal, sagittal, and axial planes. The threshold of statistical significance was set to p<0.05. RESULTS: Patients with right and left MTLE showed a reduction in volume of the entorhinal (p<0.001) and perirhinal (p<0.01) cortices ipsilateral to the HA, compared with normal controls. Patients with right MTLE exhibited a significant asymmetry of all studied structures; the right hemisphere structures had smaller volume than their left side counterparts. We did not observe linear correlations between the volumes of different structures of the medial temporal lobe in patients with MTLE. CONCLUSION: Patients with refractory MTLE have damage in the temporal lobe that extends beyond the hippocampus, and affects the regions with close anatomical and functional connections to the hippocampus.

Adult↗
PubMed1998

Lamina-specific cell adhesion on living slices of hippocampus.

Laminar distribution of fiber systems is a characteristic feature of hippocampal organization. Ingrowing afferents, e.g. the fibers from the entorhinal cortex, terminate in specific layers, which implies the existence of laminar recognition cues. To identify cues that are involved in the laminar segregation of fiber systems in the hippocampus, we used an in vitro assay to study the adhesion of dissociated entorhinal cells on living hippocampal slices. Here we demonstrate that dissociated entorhinal cells adhere to living hippocampal slices with a lamina-specific distribution that reflects the innervation pattern of the entorhino-hippocampal projection. In contrast, laminae which are not invaded by entorhinal fibers are a poor substrate for cell adhesion. Lamina-specific cell adhesion does not require the neural cell adhesion molecule or the extracellular matrix glycoprotein reelin, as revealed in studies with mutants. However, the pattern of adhesive cues in the reeler mouse hippocampus mimics characteristic alterations of the entorhinal projection in this mutant, suggesting a role of layer-specific adhesive cues in the pathfinding of entorhinal fibers. Lamina-specific cell adhesion is independent of divalent cations, is abolished after cryofixation or paraformaldehyde fixation and is recognized across species. By using a novel membrane adhesion assay, we show that lamina-specific cell adhesion can be mimicked by membrane-coated fluorescent microspheres. Recognition of the adhesive properties of different hippocampal laminae by growing axons, as either a growth permissive or a non-permissive substrate, may provide a developmental mechanism underlying the segregation of lamina-specific fiber projections.

Afferent Pathways↗
PubMed2003

Adeno-associated virus vector expressing nerve growth factor enhances cholinergic axonal sprouting after cortical injury in rats.

Nerve growth factor (NGF) is known to promote both the survival of cholinergic neurons after injury and the regeneration of damaged cholinergic axons. Recent evidence has implicated NGF in the regulation of cholinergic axonal sprouting by intact neurons projecting to the hippocampus of rats, sustaining a lesion of the entorhinal cortex. We explored the possibility that NGF may regulate this lesion-induced cholinergic sprouting by injecting recombinant adeno-associated virus (rAAV) vector expressing NGF and green fluorescent protein (GFP) into the dentate gyrus of rats that were subsequently given unilateral entorhinal lesions. Sprague Dawley rats were unilaterally injected with (1) rAAV vector expressing NGF and GFP or (2) rAAV vector expressing GFP. Fourteen days after injection, the animals received lesions of the entorhinal area ipsilateral to the virus injection. Four days after lesion, GFP expression and the septodentate sprouting response in the dentate gyrus were assessed. Optical densitometric analyses revealed a significant increase in acetylcholinesterase label (a marker for cholinergic septodentate sprouting) in the ipsilateral outer molecular layer of the dentate gyrus in rats injected with rAAV vector expressing NGF. Thus, NGF-expressing rAAV vector enhanced the sprouting response of intact cholinergic neurons after unilateral entorhinal lesions in rats.

Acetylcholinesterase↗