Bilateral Ventral Hippocampus Research Articles

Laterality dissociation of ventral hippocampus inhibition in learning and memory, glial activation and neural arborization in response to chronic stress in male Wistar rats

Many studies suggest that animals exhibit lateralized behaviors during stressful situations. However, which brain structure in each hemisphere underlies such lateralized function is unclear. This study, investigated the effects of bilateral and unilateral inhibition of the ventral hippocampus (VH) on chronic restraint stress (CRS) induced memory impairment. Unilateral and bilateral VH cannulation was carried out. After a week of recovery, lidocaine hydrochloride was injected into the rat VH ten minutes before CRS induction for seven consecutive days. Behavioral (Y-maze and Morris water maze; MWM)), and histological (glial fibrillary acidic protein; GFAP, ionized calcium-binding adapter protein-1; Iba-1, as well as Golgi-Cox staining in the VH) studies were performed. The result showed no significant difference between the effect of right-only and left-only of VH inhibition induced by lidocaine on spatial learning and memory and working memory. In addition, lidocaine treated groups were significantly lower in spatial learning and memory and working memory than control groups during non-stress conditions. Furthermore, the dendritic arborization in the right-only, left-only and bilateral VH microinjected lidocaine significantly decreased after the CRS condition compared with the control group. However, lidocaine microinjection resulted in up-regulation levels of GFAP and Iba1 in the right-only, left-only and bilateral of VH and they were higher significantly than that of their control groups after CRS and during non-stress condition. Meanwhile, there is no significant difference between the effect of right-only and left-only of VH inhibition on neuronal arborization and glial cells during non-stress and after the CRS condition. In conclusion, bilateral VH inhibition can give rise to increase CRS-induced memory impairment. These findings were accompanied by elevating GFAP and Iba1 while reducing the dendritic arborization.

The effects of gastrointestinal symptoms on structural grey matter volume in youth.

Previous neuroimaging studies have examined the association between changes in brain structure and gastrointestinal symptoms (GIS), seen in disorders such as Irritable Bowel Syndrome and Irritable Bowel Disease. Studies in adults have found changes in white and grey matter volume (GMV) in patients with various gastrointestinal disorders. However, it is unclear whether GIS-related structural changes in the brain are limited to adults or could be present throughout the lifespan. Given that gastrointestinal disorders are typically diagnosed between 4 and 18years old, we investigated GIS-induced morphological changes in pre-adolescents (8-10), adolescents (12-16years) and young adults (17-21years). Using a voxel-based morphometry (VBM) analysis, we compared regional grey matter volume (GMV) between participants with GIS and controls, using structural brain images from the Philadelphia Neurodevelopmental Cohort (PNC) database. A total of 211 participants (107 participants with GISs and 104 control participants) who had undergone structural magnetic resonance imaging were analysed. VBM analysis was used to objectively analyse GMV across the whole brain and compare between participants with GIS and controls. Participants experiencing GIS showed smaller GMV in regions within the limbic system/basal ganglia (bilateral caudate, bilateral ventral hippocampus, bilateral amygdala and bilateral superior orbital frontal cortex), and larger GMV in regions within the pain-matrix (thalamus, bilateral putamen, right mid-frontal gyrus) compared to controls. These differences were most prominent in the adolescent and young adult groups compared to pre-adolescents. In conclusion, the structural differences found in participants with GIS support the need for further research into the neurophysiological impact of these symptoms.

Angiotensin (1–7) through modulation of the NMDAR–nNOS–NO pathway and serotonergic metabolism exerts an anxiolytic-like effect in rats

Although recent studies have shown that angiotensin (1–7) (Ang [1–7]) exerts anti-stress and anxiolytic-like effects, the underlying mechanisms remain elusive. The ventral hippocampus (VH) is proposed to be a critical brain region for mood and stress management through the N-methyl-d-aspartate receptor (NMDAR) signaling pathway. However, the role of VH NMDAR signaling in the effects of Ang (1–7) remains unclear. In the present study, Ang (1–7) was injected into the bilateral VH of stressed rats, or in combination with a Fyn kinase inhibitor, NMDAR antagonist, neuronal nitric oxide synthase (nNOS) inhibitor, or nitric oxide (NO) scavenger. Anxiety-like behaviors were assessed using the open field test and elevated plus maze test, while alterations in NMDAR–nNOS–NO signaling and serotonergic metabolism were examined in the VH. After 21 days of chronic restraint stress, anxiety-like behaviors were evident. Levels of phosphorylated NR2B (a key NMDAR subunit), its upstream kinase Fyn, as well as activity of nNOS and monoamine oxidase (MAO) were markedly reduced. In contrast, levels of serotonin were increased. Bilateral VH infusion of Ang (1–7) recovered NMDAR–nNOS–NO signaling and MAO-mediated serotonin metabolism, as well as reducing anxiety-like behaviors in stressed rats. These effects were diminished by blockade of MasR (Ang [1–7]-specific receptor), Fyn kinase, NMDAR, nNOS, or NO production. Altogether, these findings indicate that Ang (1–7) exerts anxiolytic effects through modulation of the NMDAR–nNOS–NO pathway and serotonergic metabolism. Future translational research should focus on the relationship between Ang (1–7), glutamatergic neurotransmission, and serotonergic neurotransmission in the VH.

Optogenetic inhibition of ventral hippocampal neurons alleviates associative motor learning dysfunction in a rodent model of schizophrenia.

Schizophrenia (SZ) is a serious and incurable mental disorder characterized by clinical manifestations of positive and negative symptoms and cognitive dysfunction. High-frequency deep brain stimulation (DBS) of the ventral hippocampus (VHP) has been recently applied as a therapeutic approach for SZ in both experimental and clinical studies. However, little is known about the precise mechanism of VHP-DBS treatment for SZ and the role of hippocampal cell activation in the pathogenesis of SZ. With optogenetic technology in this study, we tried to inhibit neuronal activity in the VHP which has dense projections to the prefrontal cortex, before measuring long stumulus-induced delay eyeblink conditioning (long-dEBC) in a rodent model of SZ. Rats were administrated with phencyclidine (PCP, 3 mg/kg, 1/d, ip) for successive 7 days before optogenetic intervention. The current data show that PCP administration causes significant impairment in the acquisition and timing of long-dEBC; the inhibition of bilateral VHP neurons alleviates the decreased acquisition and impaired timing of longd-dEBC in PCP-administered rats. The results provide direct evidence at the cellular level that the inhibition of VHP neuronal cells may be a prominent effect of hippocampal DBS intervention, and increased activity in the hippocampal network play a pivotal role in SZ.

Dorsal raphe nucleus and harm avoidance: A resting-state investigation.

The temperament dimension of harm avoidance defines an individual's biological tendency to exhibit altering levels of anxious, inhibiting, and cautious behavior. High harm avoidance and anxiety are highly comorbid, likely due to activity in similar neural circuitries involving the dorsal raphe nucleus. Despite the many investigations that have explored personality factors and brain function, none have determined the influence of ongoing activity within dorsal raphe networks on harm avoidance. The aim of this study was to explore such a relationship. In 62 healthy subjects, a series of 180 functional magnetic resonance images covering the entire brain were collected, and each subject completed the 240-item TCI-R questionnaire. Independent component analyses were performed to define the dorsal raphe network and then to determine the regions significantly correlated with harm avoidance. The independent component analyses revealed three signal intensity fluctuation maps encompassing the dorsal raphe nucleus, showing interactions with regions of the amygdala, hippocampus, nucleus accumbens, and prefrontal, insular, and cingulate cortices. Within these systems, the resting signal intensity was significantly coupled to harm avoidance in the bilateral basal amygdala, bilateral ventral hippocampus, bilateral insula, bilateral nucleus accumbens, and medial prefrontal cortex. Note that we could not measure serotonergic output, but instead measured signal changes in the dorsal raphe that likely reflect synaptic activity. These data provide evidence that at rest, signal intensity fluctuations within the dorsal raphe networks are related to harm avoidance. Given the strong relationship between harm avoidance and anxiety-like behaviors, it is possible that ongoing activity within this identified neural circuitry can contribute to an individual developing anxiety disorders.

Neural substrates of classically conditioned fear-generalization in humans: a parametric fMRI study

Recent research on classical fear-conditioning in the anxiety disorders has identified overgeneralization of conditioned fear as an important conditioning correlate of anxiety pathology. Unfortunately, only one human neuroimaging study of classically conditioned fear generalization has been conducted, and the neural substrates of this clinically germane process remain largely unknown. The current generalization study employs a clinically validated generalization gradient paradigm, modified for the fMRI environment, to identify neural substrates of classically conditioned generalization that may function aberrantly in clinical anxiety. Stimuli include five rings of gradually increasing size with extreme sizes serving as cues of conditioned danger (CS+) and safety (CS-). The three intermediately sized rings serve as generalization stimuli (GSs) and create a continuum-of-size from CS+ to CS-. Results demonstrate 'positive' generalization gradients, reflected by declines in responding as the presented stimulus differentiates from CS+, in bilateral anterior insula, dorsomedial prefrontal cortex, and bilateral inferior parietal lobule. Conversely, 'negative' gradients, reflected by inclines in responding as the presented stimulus differentiates from CS+ were instantiated in bilateral ventral hippocampus, ventromedial prefrontal cortex and precuneus cortex. These results as well as those from connectivity analyses are discussed in relation to a working neurobiology of conditioned generalization centered on the hippocampus.

Projections from ventral hippocampus to medial prefrontal cortex but not nucleus accumbens remain functional after fornix lesions in rats

Sensorimotor gating, as measured by prepulse inhibition (PPI) of startle, is deficient in human beings with schizophrenia and is greatly reduced in rats after bilateral infusion of N-methyl-D-aspartate (NMDA) into the ventral hippocampus (VH). The disruption of PPI by bilateral VH NMDA infusion is blocked by bilateral medial prefrontal cortex (mPFC) lesions, but not by bilateral lesions of the fornix, which is the principal output pathway of the hippocampal formation of the VH. Tract-tracing studies have shown the presence of additional nonfornical pathways by which the VH and neighboring structures of the amygdala may reach forebrain regions that regulate PPI, including the mPFC. To determine whether these nonfornical pathways might mediate forebrain activation after VH NMDA infusion, we examined the effects of bilateral VH NMDA infusion on c-Fos protein expression in the mPFC and nucleus accumbens (NAC) after sham vs. bilateral fornix lesions. Significant increases of c-Fos expression were observed in both the mPFC and NAC after bilateral VH NMDA infusions. Fornix lesions blocked enhanced c-Fos expression in the NAC but not the mPFC after VH NMDA infusion. The results suggest that an intact fornix may be necessary for VH activation of the NAC, but that the VH uses additional nonfornical projections to activate PPI-regulatory circuits within the mPFC.

Rewarded associative and instrumental conditioning after neonatal ventral hippocampus lesions in rats

Sprague Dawley rats were submitted to bilateral ventral hippocampus lesions 7 days after birth. This corresponds to the Lipska and Weinberger's procedure for modeling schizophrenia. The aim of the present work was to test the learning capacity of such rats with an associative Pavlovian and an instrumental learning paradigm, both methods using reward outcome (food, sucrose or polycose). The associative paradigm comprised also a second learning test with reversed learning contingencies. The instrumental conditioning comprised an extinction test under outcome devaluation conditions. Neonatally lesioned rats, once adults (over 60 days of age), showed a conditioning deficit in the associative paradigm but not in the instrumental one. Lesioned rats remained able to adapt as readily as controls to the reversed learning contingency and were as sensitive as controls to the devaluation of outcome. Such observations indicate that the active access (instrumental learning) to a reward could have compensated for the deficit observed under the “passive” stimulus–reward associative learning condition. This feature is compared to the memory management impairments observed in clinical patients.

Effects of Behavioral and Neurochemical Changes on Adult Excitotoxic Lesion of the Ventral Hippocampus

The postmortem and magnetic resonance imaging studies for schizophrenic patients showed neuropathological abnormalities including neuron loss and volume reduction in ventral hippocampus (VH), some longitudinal studies suggest these changes may be a neurodegenerative process. The present study examined the effects of adult bilateral VH lesions on a dopaminergic stimulant, methamphetamine (METH)-induced and an N-methyl-(D)-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801)-induced behavioral and neurochemical changes in rats, in order to evaluate a potential of adult VH lesion animals for a model of schizophrenia. To study the behavioral effects after bilateral VH lesions in adult rats, locomotor activity was measured individually by an infra-red sensor. Extracellular concentrations of dopamine in the nucleus accumbens (NAc) were measured using in vivo brain microdialysis. The bilateral adult VH lesion rats showed a significant enhanced hyperlocomotion in response to METH but no changes to MK-801 and phencyclidine; while bilateral adult VH lesion enhanced METH-induced increasing dopamine levels in the NAc. The bilateral adult VH lesions enhanced locomotor activity, which related to increased dopamine releases in the NAc, induced by a dopaminergic stimulant; these findings may suggest a potential of adult VH lesion animal for a model reflecting dopamine D2 receptor antagonist-responsive pathophysiology of schizophrenia by way of neurodegenerative processes.

Alteration of conditioned emotional response and conditioned taste aversion after neonatal ventral hippocampus lesions in rats

Sprague–Dawley rats were submitted to bilateral ventral hippocampus lesions 7 days after birth according to the Lipska and Weinberger’s procedure for modeling schizophrenia. The aim of the present work was to better characterize their learning capacity. A double latent inhibition study was conducted using respectively conditioned taste aversion and conditioned emotional response. In the background of this evaluation, locomotion under apomorphine and startle reactions, inhibited or not by prepulses, was also evaluated. Our experimental methods were the same as those used in previous studies from the laboratory which were found to be sensitive to pharmacological manipulations and shown by others to be unaffected by lesions of the ventral hippocampus carried out in adult rats. In contrast, neonatally lesioned rats, once adults (over 60 days old), were hyper-responsive to noise – i.e., the startle response to a 105 db(A) noise pulse was enhanced – and hyperactive under apomorphine (0.7 mg/kg). The prepulse inhibition properties of the startle remained unchanged. Lesioned rats showed a deficit but not a suppression of conditioning, similar in both tests, but latent inhibition was preserved. Such observations complement the already known memory deficit produced in this neurodevelopmental model of schizophrenia.

Role of ventral hippocampus in acquisition, consolidation and retrieval of rat's passive avoidance response memory trace

By means of local administration of tetrodotoxin (TTX) a fully reversible functional inactivation of rat's ventral hippocampus (VH) was obtained in order to characterize the role of this structure in the memorization of a conditioned passive avoidance response (PAR). In Experiment 1, on permanently cannulated animals, TTX (10 ng in 1.0 μl saline) or saline (1.0 μl) was injected uni- or bilaterally in the VH, respectively, 1 h before PAR acquisition, immediately after PAR acquisition, and 1 h before PAR retrieval, always performed 48 h after the acquisition trial. It was shown that both pre-acquisition and pre-retrieval VH uni- or bilateral blockades were followed by significant PAR retention impairment, while in post-acquisition only the bilateral blockade determined PAR retention impairment. In Experiment 2, on three different groups of rats, TTX (10 ng in 1 μl saline) was bilaterally administered, under general ketamine anesthesia (100 mg/kg b.w.), into the VH at different post-acquisition delays (0.25, 1.5, 6 h). Retrieval testing, 48 h after treatment, showed that post-acquisition bilateral VH blockade caused PAR impairment only when performed 0.25 h after acquisition. The results clearly indicate a role of VH during acquisition, consolidation and retrieval of PAR engram. The experimental evidence is discussed in comparison to previous results concerning TTX dorsal hippocampus blockade effects on rat's PAR and in relation to hippocampal connectivity with the medial septal area and the amygdala.

The Role of Interhemispheric Pathways in Generalization of Kindled Seizures in Cats and Subhuman Primates

The role of interhemispheric pathways in generalization of partial seizures was evaluated in the kindling model of epilepsy. The generalized seizure kindled from the amygdala was asymmetrical in cats with callosal bisection, destruction of massa intermedia of the thalamus or bilateral ventral hippocampus. The generalized convulsion of amygdala kindled cats became asymmetrical or changed into partial seizures by callosal bisection. The fully-kindled amygdala seizure of a split-brain epileptic baboon and rhesus monkey was a hemiconvulsion or an asymmetrical generalized convulsion. The amygdala-kindled bisymmetrical generalized convulsion of the epileptic baboon was changed into a hemiconvulsion or an asymmetrical generalized convulsion. These results indicate that the corpus callosum plays an important, although not exclusive, role in bilateralization of epileptic activity, and its role becomes more important when the animal ascends the phylogenetic scale.