Dorsal Hippocampal Formation Research Articles

Reversible Changes in Hippocampal3H-AMPA Binding Following Inhibitory Avoidance Training in the Rat

We have recently shown that inhibitory avoidance training produces a rapid, selective, and learning-specific increase in the number of3H-AMPA glutamate receptors in several subfields of the dorsal hippocampal formation in the rat. In the present study we investigated the posttraining temporal course of this enhancement by quantitative autoradiography of3H-AMPA binding. Confirming previous results, rats submitted to a step-down inhibitory avoidance paradigm showed a marked increase (50–90%) in hippocampal3H-AMPA binding that peaked 2 h posttraining. In CA3and dentate gyrus this increase persisted for at least 48 h following training. In contrast, 24 h after training the binding of3H-AMPA in the CA1subfield did not differ significantly from naive control values. In all hippocampal regions studied, the binding of3H-AMPA at 168 h posttraining reached control values. No changes were observed in the shocked or free exploration groups in comparison with naive controls. The results suggest that hippocampal AMPA receptors undergo rapid and reversible changes after inhibitory avoidance learning and give further support to the hypothesis that changes in hippocampal AMPA receptors participate in the synaptic plasticity mediating certain forms of learning and memory.

Co‐localization of somatostatin mRNA and parvalbumin in the dorsal rat hippocampus after cerebral ischemia

Following transient global ischemia most of the neurons containing somatostatin in the fascia dentata of the dorsal hippocampal formation die, while somatostatinergic neurons in the CA1 region survive. The neurons react to ischemia with a transiently reduced expression of somatostatin mRNA and peptide. We have tested the hypothesis that this selective vulnerability is solely related to those somatostatinergic neurons which do not express the calcium-binding protein parvalbumin. Postischemic changes were studied in rat dorsal hippocampus at 2 and 16 days after 10 min of global cerebral ischemia using a four-vessel occlusion model. We performed a double-staining visualizing the mRNA coding for somatostatin by non-radioactive in situ hybridization and parvalbumin protein by immunocytochemistry. Only 5% of the somatostatinergic cells in the fascia dentata contained parvalbumin. The number of somatostatinergic cells was permanently reduced following ischemia. Among surviving neurons we found cells with and without parvalbumin expression. Thus, expression of parvalbumin is not predictive for survival of somatostatinergic cells in the fascia dentata. In contrast, in CA1, 37% of the somatostatinergic cells contained parvalbumin. These cells were unaffected by the transient ischemic period. The somatostatinergic cells lacking parvalbumin showed transiently reduced mRNA levels at day 2, but recovered to control values at the 16th postischemic day. Thus, expression of the calcium-buffering protein parvalbumin coincides with resistance of somatostatinergic neurons in CA1 to transient effects of ischemia. We conclude that the calcium-buffering capacity of parvalbumin may partially contribute to the protection of somatostatinergic neurons from ischemia in the dorsal hippocampus. However, the survival of somatostatinergic cells without parvalbumin indicates the importance of other factors as well.

Hippocampal-entorhinal relationships: Electrophysiological analysis of the ventral hippocampal projections to the ventral entorhinal cortex

The hippocampal output to the ventral entorhinal area was studied in the guinea-pig by field potential analysis. Perforant path volleys, synaptically elicited by stimulation of dorsal psalterium fibers, were used to obtain activation of the lamellar circuit of the dorsal hippocampal formation and the subsequent activation, through intrahippocampal longitudinal connections, of pyramidal neurons in the ventral hippocampus. The latter activation was obtained by low-frequency (0.1–2.0/s) repetitive dorsal psalterium stimulation. A response occurred in the ventral entorhinal area only following low-frequency (0.1–2.0/s) repetitive stimulation. The ventral entorhinal response occurred both in the medial and lateral divisions of the ventral entorhinal area. It consisted of a negative wave with associated unit firing in all cellular layers of the medial and lateral ventral entorhinal area. The latency of the entorhinal response increased moving from the deep to the superficial layers. These findings suggest the generation of excitatory synaptic effects in temporal sequence in the deep and then in the superficial layers of the entorhinal cortex. The ventral entorhinal response showed longer latency and a higher threshold than the ventral hippocampal response, and was eliminated by interruption of the caudally directed ventral hippocampal projections. These data suggest that the ventral entorhinal response was mediated by projections from the ventral hippocampus. The results show that the ventral hippocampal output evokes excitatory synaptic effects in all cellular layers of the medial and the lateral ventral entorhinal area. The massive involvement of the entorhinal area, together with the widespread distribution of the entorhinal projections, support the idea that the entorhinal cortex represents a crucial link between the hippocampus and the other brain regions.

Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning.

The effects of hippocampal lesions on the conditioning of fear responses (freezing responses) to contextual stimuli (static, continuously present stimuli) were examined in three conditioning paradigms: forward pairing of a phasic tone conditioned stimulus (CS) with a footshock unconditioned stimulus (US), unpaired presentations of the CS and US, or presentations of the US alone. All three procedures resulted in the acquisition of conditioned freezing to contextual stimuli. Lesions of the dorsal hippocampus prevented the acquisition of contextual conditioning in the Paired procedure, as reported previously, but not in the Unpaired or US Alone procedures. In the Paired procedure, static contextual cues occur in the background, with the phasic tone CS being the primary stimulus that enters into the association with the US. However, in the other two procedures, where there is no phasic CS, the primary associations with the US involve static contextual stimuli, which are therefore in the foreground. We refer to these types of contextual conditioning as background and foreground contextual conditioning, respectively, and argue that the hippocampus is only involved in background contextual conditioning. These results have implications for understanding both fear conditioning and hippocampal function.

A low-affinity nerve growth factor receptor antibody is internalized and retrogradely transported selectively into cholinergic neurons of the rat basal forebrain

The mechanism by which nerve growth factor transduces its signal in responsive cells is yet to be clearly defined. However, it has been suggested that the internalization of nerve growth factor, the first step in the retrograde flow of nerve growth factor, is a property of the high-affinity receptors, p140 trka. Here we show that when a monoclonal antibody (MC 192), which immunoprecipitates p75 NGFR (the low-affinity 75,000 mol. wt nerve growth factor receptor protein) and not p140 trka, was administered into the dorsal hippocampal formation of the rats, it was internalized and retrogradely transported to the cell bodies residing in the medial septum-diagonal band complex. The topographic organization and the localization of these neurons containing retrogradely transported p75 NGFR antibody were strikingly similar to those nerve cells immunostained for choline acetyltransferase in the immediately-adjacent section, indicating that the neurons which contained p75 NGFR antibody were cholinergic neurons. A double-label immunocytochemistry confirmed this conclusion. On the other hand, none of the parvalbumin-positive GABAergic neurons contained retrogradely transported p75 NGFR antibody. Moreover, in contrast to specific transport of p75 NGFR antibody into cholinergic neurons, when wheat germ agglutinin-colloidal gold was injected into the hippocampus at the same levels, it was taken up and retrogradely transported into both choline acetyltransferase-positive cholinergic and parvalbumin-immunoreactive GABAergic neurons in the medial septum-diagonal band complex.

Decreased seizure threshold after intrahippocampal colchicine injection in rats

Wet dog shaking elicited by perforant path stimulation is little affected by bilateral injection of colchicine into the dorsal hippocampal formation but virtually eliminated by bilateral injection into the ventral hippocampal formation. Injection of colchicine into either dorsal or ventral hippocampal formation lowers the threshold for eliciting forelimb clonus with rearing. This effect is more pronounced 8 weeks postinjection than 2 weeks postinjection when colchicine is injected in the ventral hippocampal formation. This suggests that inappropriate reactive synaptogenesis and/or neuronal degeneration continues for an extended period after intrahippocampal injection of colchicine, especially in the ventral hippocampal formation.

Effect of destruction of dentate granule cells on kindling induced by stimulation of the perforant path

Bilateral destruction of dentate granule cells in both the dorsal and ventral hippocampal formation had no effect on the threshold for hippocampal afterdischarge before or after kindling. Neither did it affect the number of stimulations required to attain kindling. However, the duration of afterdischarge was significantly longer in colchicine-lesioned animals compared to those receiving artificial cerebrospinal fluid. This was true for the threshold for afterdischarge as well as at the first and last kindling trials. These results suggest that dentate granule cells may inhibit the duration of afterdischarge induced by perforant path stimulation or that other postlesion changes occur which result in a prolongation of hippocampal afterdischarge.

Evidence for specific N-terminal galanin fragment binding sites in the rat brain

The existence and widespread distribution of specific [ 125I]galanin-(1–15) fragment binding sites in the rat brain was demonstrated by using [ 125I]galanin-(1–15) as a radioligand in quantitative receptor autoradiographical studies. These binding sites were also present in several areas lacking or having very few [ 125I]galanin-(1–29) binding sites, such as the dorsal hippocampal formation, the neocortcx and the ncostriatum. [ 125I]Galanin-(1–15) binding sites showed a high selectivity for the fragment, since galanin-(1–15) could displace 80% of the binding whereas porcine galanin-(1–29) could only displace 30%. The binding was saturablc with a K d of 0.63 ± 0.02 nM and a B max of 15.3 ± 1.7 fmol/mg in sections from the dorsal hippocampal formation. Thus, a new type of galanin receptor selective for N-terminal galanin fragments may exist in the rat brain.

Calretinin is present in non-pyramidal cells of the rat hippocampus—I. A new type of neuron specifically associated with the mossy fibre system

Calretinin-containing cells were visualized with immunocytochemistry in the rat dorsal hippocampal formation. Calretinin immunoreactivity was present exclusively in non-pyramidal cells in all layers of the dentate gyrus and the CA1–3 areas. Calretinin-positive neurons and processes were most abundant in the hilus of the dentate gyrus and in the stratum lucidum of the CA3 region. Several calretinin-immunoreactive cells were located within the hippocampal fissure. A distinct band of calretinin-immunoreactive fibres occupied the superficial part of the granule cell layer and the lowest part of the molecular layer. Closer examination of the calretinin-positive cells revealed that they formed two distinct cell groups. One group of cells, found exclusively in the stratum lucidum of the CA3 area and in the hilus of the dentate gyrus, was covered with numerous spines. Their somata and dendrites were restricted to stratum lucidum and to the hilus. Cells of the other group had smooth, often varicose, radially running dendrites, and were present in all areas and layers of the hippocampal formation. Two to three thick primary dendrites arose from the irregularly shaped cell body of spiny cells and emitted fine secondary branches only distally (70–100 μm) from the soma, where they formed a profuse network. The extensive dendritic tree of the cells spread horizontally within stratum lucidum and span a distance of 400–600 μm both in the septotemporal and in the transverse directions. The layer-specific location of these cells and their processes suggested that the majority of their input may derive from mossy fibres. This presumption has been confirmed by electron microscopic examination. A large number of asymmetrical synapses were found to cover the soma, the dendritic shafts and the spines (four to six synapses/spine) of the cells. A large proportion of the synapses were formed by boutons, which showed the distinctive features of mossy fibre terminals. Three to six primary dendrites arose from the multipolar, bipolar or pyramidal-shaped somata of spine-free cells, which were smaller than the somata of spiny cells. The smooth and frequently varicose dendrites branched proximally and ran primarily radially. Dendrites ascended or descended through several layers and received both asymmetrical and symmetrical synapses. In the CA1 subfield, the vertically running dendrites frequently contacted other calretinin-immunoreactive spine-free dendrites or cell bodies. Two or three calretinin-immunoreactive dendrites were often seen to be attached for over 100 or, occasionally, 200 μm and several puncta adherentia were observed between them using the electron microscope. The axons of the cells arborized in all layers, had small en passant varicosities, and were found to establish symmetrical synapses with dendritic shafts. In summary, spine-free calretinin-immunoreactive cells showed the characteristic features of GABAergic interneurons both at the light and the electron microscopic levels. Axon terminals of the dense calretinin-immunoreactive fibre network in the superficial part of the granule cell layer formed synapses with dendritic shafts and spines of putative granule cells. The characteristic location and features of the synapses, i.e. a very thick and dense postsynaptic specialization, suggest that these fibres derive from the supramammillary nucleus, rather than from calretinin-immunoreactive neurons in the hippocampus.

Calretinin is present in non-pyramidal cells of the rat hippocampus—II. Co-existence with other calcium binding proteins and gaba

The possible co-existence of calretinin with other calcium binding proteins, parvalbumin and calbindin D28k, and with GABA, was studied in non-pyramidal cells of the rat dorsal hippocampal formation, using the mirror technique. The majority of the calretinin-containing neurons (83%) were found to be immunoreactive for GABA (79% in the dentate gyrus, 84% in the CA2–3, and 88% in the CA1 subfield). Most of the GABA-negative calretinin-immunoreactive neurons were located in the hilus of the dentate gyrus and in stratum lucidum of the CA3 subfield. Detailed analysis of the calretinin-immunoreactive cells of these subfields revealed that the two morphologically distinct types of calretinin neurons, i.e. the spiny and the spine-free cells, differ in their immunoreactivity for GABA. The overwhelming majority (92%) of the spine-free neurons were GABA-positive, whereas the immuno-reactivity of spiny cells was ambiguous. At the sensitivity threshold of the immunocytochemical techniques used in the present study, most of the spiny cells (89%) had to be considered as GABA-negative, although the staining intensity in their cell bodies was somewhat above background level. Colchicine treatment resulted in a degeneration of calretinin-immunoreactive neurons; therefore, its effect on the GABA content of spiny neurons could not be evaluated. Nevertheless, the observations suggest that calretinin-containing neurons are heterogeneous both morphologically and neurochemically. Examination of the co-existence of calcium binding proteins revealed that none of the hippocampal cells contained both calretinin and parvalbumin in any regions of the hippocampal formation. Some overlap was detected between the calretinin- and the calbindin D28k-containing cell populations, 5.1% of the former and 6.2% of the latter were immunoreactive for both calcium binding proteins. This may be due to a small degree of cross-reactivity of the calbindin D28k antiserum with calretinin. Thus, our results demonstrate that the majority of calretinin-immunoreactive neurons are GABAergic and represent a subpopulation of non-pyramidal cells with no or only a negligible overlap with the subpopulations containing the other calcium binding proteins, parvalbumin and calbindin.

Perinatal Hypothyroidism Decreases Hippocampal Mossy Fiber Zinc Density in Rats

The effect of perinatal hypothyroidism on hippocampal mossy fiber zinc density was examined in rats. Timed pregnant Sprague-Dawley rat dams were given water containing either 0.02% propylthiouracil (PTU) or vehicle from gestational day 18 until their litters were weaned on postnatal day 31. Hippocampal mossy fiber zinc density was reduced by 75% in both the dorsal and ventral hippocampal formation CA3 stratum lucidum region of 31-day-old PTU-treated rats compared to untreated controls. Perinatal hypothyroidism did not alter hippocampal tissue zinc concentration, indicating that the PTU-induced reduction in mossy fiber zinc was not a consequence of reduced hippocampal zinc concentration. At 120 days of age, 3 months after discontinuation of PTU treatment, hippocampal mossy fiber zinc density remained significantly reduced by 33-45% in PTU-treated rats compared to control. These data indicate that perinatal hypothyroidism causes a long-lasting reduction in hippocampal mossy fiber zinc density.

Prenatal ethanol exposure during the last third of gestation in rat reduces hippocampal NMDA agonist binding site density in 45-day-old offspring

The effect of ethanol exposure during different periods of prenatal or postnatal development on hippocampal N-methyl-D-aspartate (NMDA) receptor binding was studied in rat. Fetal rat pups were exposed to ethanol for different periods of time during gestation via maternal consumption of a 3.35% ethanol liquid diet. In a separate experiment, neonatal pups were fed 2.51 g ethanol/kg body weight/day from Postnatal Day (PD) 4 to PD 10 via intragastric feeding tube. These two ethanol administration paradigms produced average peak maternal and pup blood ethanol concentrations of 39 mg/dl and 57 mg/dl, respectively. At 45 days of age, offspring from each treatment group were sacrificed for measurements of hippocampal NMDA-sensitive [ 3H]-glutamate binding site density using in vitro radiohistochemical techniques. As observed previously, prenatal ethanol exposure throughout gestation resulted in NMDA-sensitive [ 3H]-glutamate binding site reductions in the apical dendritic field regions of dentate gyrus, hippocampal CA 1 and subiculum of dorsal hippocampal formation compared to the ad lib or pair-fed control groups. NMDA-sensitive [ 3H]-glutamate binding was not different than control in rats exposed to ethanol during the first half of gestation only. Prenatal ethanol exposure during the last half or the last third of gestation resulted in NMDA-sensitive [ 3H]-glutamate binding site reductions comparable to the binding site reductions observed in rats exposed to ethanol throughout gestation. Hippocampal NMDA-sensitive [ 3H]-glutamate binding site density in postnatal ethanol-exposed rats was not different than the suckling or gastrostomy control groups. These results suggest that the critical period of vulnerability to ethanol-induced reductions in hippocampal NMDA receptor binding occurs during the last third of gestation in rat, which, in terms of human hippocampal development, is a period of time roughly equivalent to the fifth and six months of human gestation.

Subpopulations of GABAergic neurons containing parvalbumin, calbindin D28k, and cholecystokinin in the rat hippocampus

The possible coexistence of calbindin D28k with parvalbumin and of calbindin D28k with cholecystokinin was studied in nonpyramidal cells of the rat dorsal hippocampal formation. Neighbouring Vibratome sections were immunostained either for calbindin D28k and parvalbumin or for calbindin D28k and cholecystokinin. The cells, halved during sectioning, were identified in both sections immunostained for different antigens. The coexistence of calbindin D28k and parvalbumin in the same neuron was rare throughout the hippocampal formation with the exception of stratum oriens of the CA1 region, where 9.6% of the parvalbumin-immunoreactive cells also contained calbindin D28k. In stratum radiatum of the CA3 region, calbindin D28k and cholecystokinin coexisted in 12.5% and 21.2% of the calbindin D28k and cholecystokinin-immunoreactive cells, respectively. In other regions of the hippocampal formation, the two markers coexisted in less than 5% of the cells of either type. The present results demonstrate that calbindin D28k-, parvalbumin- and cholecystokinin-containing nonpyramidal cells represent largely nonoverlapping cell populations and may thus be involved in different inhibitory circuits.

Host Brain Regulation of Fetal Locus Coeruleus Neurons Grafted to the Hippocampus in 6-Hydroxydopamine-Treated Rats. An Intracerebral Microdialysis Study.

Release properties of intrahippocampal transplants of noradrenergic neurons were monitored by microdialysis in awake and halothane-anaesthetized rats. Fetal locus coeruleus neurons were implanted as a cell suspension into hippocampi deprived of their innate noradrenalin (NA) innervation by intraventricular 6-hydroxydopamine treatment. Dialysis probes of the loop type were implanted into the dorsal hippocampus 1 - 2 days before each experiment, i.e. 7 - 11 months after grafting. Age-matched intact and lesion-only animals served as controls. Microscopic analysis showed a graft-derived tyrosine hydroxylase immunoreactive, presumably noradrenergic, fibre network throughout the dorsal hippocampal formation, surrounding the probe site. The innervation density varied from sub- to supranormal. The grafts restored baseline NA release in the graft-reinnervated hippocampus to near-normal levels both in awake and halothane-anaesthetized animals. Potassium chloride (100 mM) in the perfusion fluid induced a dramatic increase in NA release that was similar in magnitude in the grafted and intact hippocampi. A NA uptake blocker (desipramine) added to the perfusion fluid at 5 microM induced a similar increase in NA output in the grafted and intact hippocampi, and the output was substantially reduced by tetrodotoxin, added at 1 microM in the presence of uptake blockade. Electrical stimulation of the lateral habenular nucleus (15 Hz, 0.5 mA) in halothane-anaesthetized rats induced a significant increase in NA output both in the intact and grafted hippocampi. This effect was abolished by transection of the fasciculus retroflexus, which carries the efferent projections of the habenular complex. Behavioural activation through handling induced a consistent increase in NA release only in the intact animals, but in a few grafted rats (which also responded to habenular stimulation) the NA output was clearly elevated by handling. Forced immobilization induced a significant increase in NA output both in the intact and grafted hippocampi, but in the grafted ones the response was somewhat smaller and more transient. In the same set of animals, swimming in warm water (25 - 30 degrees C) induced a sharp increase in NA output in the intact animals, whereas only one of the grafted rats responded by increased NA output. The results indicate that the locus coeruleus grafts, despite their ectopic location, can become functionally integrated with the host brain, and that the activity of the transplanted noradrenergic neurons can, under some circumstances, be modulated from the host brain in response to environmental challenges.

Prenatal ethanol exposure decreases hippocampal NMDA-sensitive [ 3H]-Glutamate binding site density in 45-day-old rats

The effect of prenatal ethanol exposure on N-methyl-D-aspartate (NMDA)-sensitive [3H]-glutamate receptor binding site density was studied in rat brain. Pregnant Sprague-Dawley rats were fed a liquid diet containing 3.35% ethanol throughout gestation. This diet produced maternal peak blood ethanol levels of about 39 mg/dl eight hours after the administration of the liquid diet. Pair-fed dams received an isocalorically matched liquid diet and an ad lib lab chow group served as control for the paired feeding technique. At 45 days of age, offspring from each of the three diet groups were sacrificed and brain NMDA-sensitive [3H]-glutamate binding site density measured using in vitro radiohistochemical techniques. NMDA-sensitive [3H]-glutamate binding site density was reduced significantly by 19 to 29% in the apical dendritic field regions of dentate gyrus, hippocampal CA1 and subiculum of dorsal hippocampal formation of fetal alcohol rats compared to pair-fed and ad lib controls. NMDA-sensitive [3H]-glutamate binding site density was not significantly different among the three groups in the ventral hippocampal formation, posterior neocortex, lateral entorhinal cortex or cerebellum. These results are consistent with our previous observations of a reduction in total [3H]-glutamate receptor binding site density in the dorsal hippocampal formation of fetal alcohol rats, as well as more recent electrophysiological observations of a decrease in the sensitivity of fetal alcohol hippocampal slices to NMDA.

Septohippocampal cholinergic axonal regeneration through peripheral nerve bridges: Quantification and temporal development

Axons of the adult mammalian CNS have been shown to regrow vigorously into peripheral nerve grafts. Using a cholinergic septohippocampal model for adult CNS regeneration, involving complete denervation of the hippocampal formation from its basal forebrain cholinergic afferents, this study has established quantitative parameters and a temporal baseline of cholinergic fiber regeneration into the dorsal hippocampal tissue through a peripheral sciatic nerve graft. In nerve-implanted animals (i) the nerve grafts are maximally invaded by AChE-positive fibers between 2 weeks and 1 month postlesion, (ii) the fibers entering the hippocampal formation from the graft show a peak numerical increase and rate of elongation around the first month and/or in the proximal hippocampal region, (iii) an apparently normal innervation pattern and fiber density in the most rostral 1.5 mm of the dorsal hippocampal formation is reached by 6 months postlesion. The present study provides a basis for future quantitative comparisons of manipulations of different components of the system, e.g., the contributing neurons, the bridging material, and the receiving central nervous tissue. The temporal/spatial pattern of fiber regeneration suggests that the hippocampal CNS tissue can be a good axonal growth-promoting environment, albeit with temporal and/or spatial limitations, and is therefore not an immutably restrictive environment for axonal regeneration.

Differential effects of colchicine lesions of dentate granule cells on wet dog shakes and seizures elicited by direct hippocampal stimulation

Direct electrical stimulation of either the dorsal or ventral hippocampal formation elicits wet dog shakes and overt seizures. Destruction of dentate granule cells in the dorsal hippocampal formation does not significantly reduce the number of wet dog shakes elicited by ventral hippocampal stimualtion. However, destruction of dentate granule cells in the ventral hippocampus virtually eliminates wet dog shaking elicited by dorsal hippocampal stimulation. Destruction of either dorsal or ventral dentate granule cells lowers the threshold for eliciting forelimb clonus with rearing. These results suggest that dentate granule cells in the ventral hippocampus are essential for wet dog shakes elicited by intrahippocampal stimulation. However, dentate granule cells throughout the hippocampal formation appear to play an important inhibitory role in the spread of seizure activity within the hippocampus.

Medial septal neurons containing N-acetyl-aspartyl-glutamate-like immunoreactivity project to the hippocampal formation in the rat

We have examined the distribution of N-acetyl-aspartyl-glutamate (NAAG)-like immunoreactive cell bodies in the medial septal nucleus and the nucleus of the diagonal band of Broca of the rat and assessed the involvement of these cells in the septo-hippocampal pathway. A series of experiments was carried out using immunohistochemistry alone or combined with the retrograde transport of a protein-gold complex injected into the dorsal hippocampal formation. A large number of NAAG-positive cells was observed in the medial septum and the diagonal band. Quantitative analysis revealed that 26% of the NAAG-like immunoreactive cells in the medial septum project to the dorsal hippocampal formation. These results demonstrate that the dipeptide NAAG is a major component of the rat septo-hippocampal pathway.

Locomotor activity in rats after administration of nicotinic agonists intracerebrally

1. Nicotine (0.13 and 0.4 mg kg-1, s.c.) increased the ambulatory component of locomotor activity in rats previously exposed to the drug. Nicotine did not increase repeated movements reliably. 2. An infusion of either nicotine (8 micrograms) or the potent nicotinic agonist cytisine (4 micrograms) into the ventral tegmental area of the forebrain increased ambulation but not repeated movements. 3. An infusion of nicotine or cytisine into the nucleus accumbens, striatum, dorsal hippocampal formation or motor thalamus did not increase ambulatory or repeated movements. 4. Mecamylamine (0.1-1.0 mg kg-1, s.c.) blocked increases in locomotor activity produced by an infusion of nicotine or cytisine into the ventral tegmental area. 5. The locomotor activity produced by systemically administered nicotine may be mediated, in part, through nicotinic receptors located in the ventral tegmental area of the mesolimbic dopamine system.

Perinatal Hypothyroidism Decreases Hippocampal <sup>3</sup>H-Vinylidene Kainic Acid Binding in Rats

The effect of perinatal hypothyroidism on the number and distribution of hippocampal kainic acid binding sites was examined in rats. Timed pregnant Sprague-Dawley rat dams were given water containing either 0.02% propylthiouracil (PTU) or untreated water from gestational day 18 until their litters were weaned at postnatal day 31. The offspring were sacrificed at 31 or 120 days of age, blood samples collected and their brains frozen. In the 31-day-old rats, serum thyroxine, serum triiodothyronine, total body weight and whole brain weight all indicated that the PTU-treated rats were hypothyroid. Hippocampal kainic acid binding was analyzed in sections of dorsal and ventral hippocampal formation by in vitro 3H-vinylidene kainic acid (VKA) autoradiography. Compared to the untreated controls, specific 3H-VKA binding was reduced by 43% in the ventral hippocampal formation stratum lucidum of 31-day-old PTU-treated rats. Specific 3H-VKA binding was not different in the dorsal hippocampal formation. Saturation of 3H-VKA binding studies indicated that the decrease-induced by PTU treatment--in ventral hippocampal 3H-VKA binding was due to a reduction in the total number of 3H-VKA binding sites. At 120 days of age, 3 months after the cessation of the PTU treatment, serum thyroid hormone levels were not different than those of controls, indicating a recovery of thyroid hormone function after the perinatal PTU treatment. However, specific 3H-VKA binding remained significantly reduced in the ventral hippocampal formation of 120-day-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)