Differential expression of GABAA receptor subunits δ and α6 mediates tonic inhibition in parvalbumin and somatostatin interneurons in the mouse hippocampus.

Inhibitory γ-aminobutyric acid (GABA)-ergic interneurons mediate inhibition in neuronal circuitry and support normal brain function. Consequently, dysregulation of inhibition is implicated in various brain disorders. Parvalbumin (PV) and somatostatin (SST) interneurons, the two major types of GABAergic inhibitory interneurons in the hippocampus, exhibit distinct morpho-physiological properties and coordinate information processing and memory formation. However, the molecular mechanisms underlying the specialized properties of PV and SST interneurons remain unclear. This study aimed to compare the transcriptomic differences between these two classes of interneurons in the hippocampus using the ribosome tagging approach. The results revealed distinct expressions of genes such as voltage-gated ion channels and GABAA receptor subunits between PV and SST interneurons. Gabrd and Gabra6 were identified as contributors to the contrasting tonic GABAergic inhibition observed in PV and SST interneurons. Moreover, some of the differentially expressed genes were associated with schizophrenia and epilepsy. In conclusion, our results provide molecular insights into the distinct roles of PV and SST interneurons in health and disease.

Connectivity and synaptic features of hilar mossy cells and their effects on granule cell activity along the hippocampal longitudinal axis.

The hippocampus is an elongated brain structure which runs along a ventral-to-dorsal axis in rodents, corresponding to the anterior-to-posterior axis in humans. A glutamatergic cell type in the dentate gyrus (DG), the mossy cells (MCs), establishes extensive excitatory collateral connections with the DG principal cells, the granule cells (GCs), and inhibitory interneurons in both hippocampal hemispheres along the longitudinal axis. Although coupling of two physically separated GC populations via long-axis projecting MCs is instrumental for information processing, the connectivity and synaptic features of MCs along the longitudinal axis are poorly defined. Here, using channelrhodopsin-2 assisted circuit mapping, we showed that MC excitation results in a low synaptic excitation-inhibition (E/I) balance in the intralamellar (local) GCs, but a high synaptic E/I balance in the translamellar (distant) ones. In agreement with the differential E/I balance along the ventrodorsal axis, activation of MCs either enhances or suppresses the local GC response to the cortical input, but primarily promotes the distant GC activation. Moreover, activation of MCs enhances the spike timing precision of the local GCs, but not that of the distant ones. Collectively, these findings suggest that MCs differentially regulate the local and distant GC activity through distinct synaptic mechanisms. KEY POINTS: Hippocampal mossy cell (MC) pathways differentially regulate granule cell (GC) activity along the longitudinal axis. MCs mediate a low excitation-inhibition balance in intralamellar (local) GCs, but a high excitation-inhibition balance in translamellar (distant) GCs. MCs enhance the spiking precision of local GCs, but not distant GCs. MCs either promote or suppress local GC activity, but primarily promote distant GC activation.

Hypothalamic Glutamate/GABA Cotransmission Modulates Hippocampal Circuits and Supports Long-Term Potentiation.

Subcortical input engages in cortico-hippocampal information processing. Neurons of the hypothalamic supramammillary nucleus (SuM) innervate the dentate gyrus (DG) by coreleasing two contrasting fast neurotransmitters, glutamate and GABA, and thereby support spatial navigation and contextual memory. However, the synaptic mechanisms by which SuM neurons regulate the DG activity and synaptic plasticity are not well understood. The DG comprises excitatory granule cells (GCs) as well as inhibitory interneurons (INs). Combining optogenetic, electrophysiological, and pharmacological approaches, we demonstrate that the SuM input differentially regulates the activities of different DG neurons in mice of either sex via distinct synaptic mechanisms. Although SuM activation results in synaptic excitation and inhibition in all postsynaptic cells, the ratio of these two components is variable and cell type-dependent. Specifically, dendrite-targeting INs receive predominantly synaptic excitation, whereas soma-targeting INs and GCs receive primarily synaptic inhibition. Although SuM excitation alone is insufficient to excite GCs, it enhances the GC spiking precision and reduces the latencies in response to excitatory drives. Furthermore, SuM excitation enhances the GC spiking in response to the cortical input, thereby promoting induction of long-term potentiation at cortical-GC synapses. Collectively, these findings provide physiological significance of the cotransmission of glutamate/GABA by SuM neurons in the DG network.SIGNIFICANCE STATEMENT The cortical-hippocampal pathways transfer mnemonic information during memory acquisition and retrieval, whereas subcortical input engages in modulation of communication between the cortex and hippocampus. The supramammillary nucleus (SuM) neurons of the hypothalamus innervate the dentate gyrus (DG) by coreleasing glutamate and GABA onto granule cells (GCs) and interneurons and support memories. However, how the SuM input regulates the activity of various DG cell types and thereby contributes to synaptic plasticity remains unexplored. Combining optogenetic and electrophysiological approaches, we demonstrate that the SuM input differentially regulates DG cell dynamics and consequently enhances GC excitability as well as synaptic plasticity at cortical input-GC synapses. Our findings highlight a significant role of glutamate/GABA cotransmission in regulating the input-output dynamics of DG circuits.

Frequent exposure to varied home cage sizes alters pain sensitivity and some key inflammation-related biomarkers.

BACKGROUND: Nature and size of rodent cages vary from one laboratory or country to another. Little is however known about the physiological implications of exposure to diverse cage sizes in animal-based experiments. METHOD: Here, two groups of male Swiss mice (Control group - Cage stationed, and Test group - Cage migrated) were used for this study. The cage-migrated mice were exposed daily to various cage sizes used across laboratories in Nigeria while the cage-stationed mice exposed daily to different but the same cage size and shape. At the end of the 30 days exposure, top-rated paradigms were used to profile changes in physiological behaviours, and this was followed by evaluation of histological and biochemical metrics. RESULTS: The study showed a significant (p < 0.05) decrease in blood glucose levels (at 60 and 120 min of oral glucose tolerance test) in the cage-migrated mice compared to cage-stationed mice. Strikingly, peripheral oxidative stress (plasma malondialdehyde) and pain sensitivity (formalin test, hot-and-cold plate test, and von Frey test) decreased significantly in cage-migrated mice compared to cage-stationed animals. Also, the pro-inflammation mediators (IL-6 and NF-κB) increased significantly in cage-migrated mice compared to cage-stationed mice. However, emotion-linked behaviours, neurotransmitters (serotonin, noradrenaline and GABA), brain and plasma electrolytes were not significantly difference in cage-migrated animals compared to cage-stationed mice. CONCLUSION: Taken together, these results suggest that varied size cage-to-cage exposure of experimental mice could affect targeted behavioural and biomolecular parameters of pain and inflammation, thus diminishing research reproducibility, precipitating false negative/positive results and leading to poor translational outcomes.

Oral Ingestion of Cannabis sativa: Risks, Benefits, and Effects on Malaria-Infected Hosts.

Background: The emergence of a multidrug-resistant strain of Plasmodium falciparum (Pf Pailin) raises concern about malaria control strategies. Unfortunately, the role(s) of natural plants/remedies in curtailing malaria catastrophe remains uncertain. The claims of potential antimalarial activity of Cannabis sativa in vivo have not been well established nor the consequences defined. This study was, therefore, designed to evaluate the effects of whole cannabis consumption on malaria-infected host. Methods: Thirty mice were inoculated with dose of 1×107 chloroquine-resistant Plasmodium berghei ANKA-infected erythrocyte and divided into six treatment groups. Cannabis diet formulations were prepared based on weighted percentages of dried cannabis and standard mice diet and the study animals were fed ad libitum. Chemosuppression of parasitemia, survival rates, parasite clearance, and recrudescence time were evaluated. Histopathological studies were performed on the prefrontal cortex (PFC) and hippocampus of the animals after 14 days' consumption of cannabis diet formulation by naive mice. Results: There was a significant difference (p<0.05) in the day-4 chemosuppression of parasitemia between the animals that were fed C. sativa and chloroquine relative to the untreated controls. There was also a significant difference in the survival rate (p<0.05) of animals fed C. sativa diet (40%, 20%, 10%, and 1%) in contrast to control animals on standard mice diet. A parasite clearance time of 2.18±0.4 was recorded in the chloroquine treatment group, whereas recrudescence in chloroquine group occurred on day 7. There were slight histomorphological changes in the PFC and cell densities of the dentate gyrus of the hippocampus of animals that were fed C. sativa. Conclusions: C. sativa displayed mild antimalarial activity in vivo. There was evident reduction in symptomatic manifestation of malaria disease, though unrelated to levels of parasitemia. This disease tolerance status may be beneficial, but may also constitute a transmission burden through asymptomatic carriage of parasites by habitual cannabis users.

Cannabis-induced Moto-Cognitive Dysfunction in Wistar Rats: Ameliorative Efficacy of Nigella Sativa.

BACKGROUND: Cannabis is a widely used illicit drug with various threats of personality syndrome, and Nigella sativa has been widely implicated as having therapeutic efficacy in many neurological diseases. The present study investigates the ameliorative efficacy of Nigella sativa oil (NSO) on cannabis-induced moto-cognitive defects. METHODS: Scopolamine (1 mg/kg i.p.) was given to induce dementia as a standard base line for cannabis (20 mg/kg)-induced cognitive impairment, followed by an oral administration of NSO (1 ml/kg) for 14 consecutive days. The Morris water maze (MWM) paradigm was used to assess the memory index, the elevated plus maze was used for anxiety-like behaviour, and the open field test was used for locomotor activities; thereafter, the rats were sacrificed and their brains were removed for histopathologic studies. RESULTS: Cannabis-like Scopolamine caused memory impairment, delayed latency in the MWM, and anxiety-like behaviour, coupled with alterations in the cerebello-hippocampal neurons. The post-treatment of rats with NSO mitigated cannabis-induced cognitive dysfunction as with scopolamine and impaired anxiety-like behaviour by increasing open arm entry, line crossing, and histological changes. CONCLUSIONS: The observed ameliorative effects of NSO make it a promising agent against moto-cognitive dysfunction and cerebelo-hippocampal alterations induced by cannabis.

Honey prevents neurobehavioural deficit and oxidative stress induced by lead acetate exposure in male Wistar rats- a preliminary study.

This research sought to investigate the possible neuroprotective effects of honey against lead (Pb)-induced neurotoxicity. Twenty four male Wistar rats were divided into four groups: Control group that received 1 ml/kg distilled orally for 28 days; while groups II-IV received 0.2% lead in drinking water and 1 ml/kg of distilled water, 1 ml/kg of honey, 1.5 ml/kg of honey respectively for 28 days. Anxiety and exploratory activities were determined in the open field test. Memory function was determined using Morris water maze after which the animals were sacrificed. The brains were then excised, homogenized and Lipid peroxidation (MDA), Superoxide dismutase (SOD), Catalase, Glutathione (GSH) and Glutathione -S- Transferase (GST) activities were determined in the brains. Results showed that lead exposure causes decrease in locomotor and exploratory activities; increase anxiety, memory impairment, lipid peroxidation and decrease antioxidant activities. However, co-administration of honey with lead inhibited neurotoxicity as indicated by the improvement in memory function as evidenced by decreased latency period and increased in time spent in target quadrant in honey-fed rats compared to the lead-exposed animals. Furthermore, honey increased locomotion, exploration and decreased anxiety in lead-exposed rats as indicated by the frequency of rearing, freezing duration and the number of line crossed by animals. Also administration of honey improves antioxidant activities as shown by increased brain SOD, GST and GSH activities compared to the lead-treated groups but no significant effect on MDA level. It can be concluded that honey has neuroprotective effects against lead-induced cognitive deficit probably by enhancing antioxidant activities.

Amitriptyline and phenytoin prevents memory deficit in sciatic nerve ligation model of neuropathic pain.

BACKGROUND: Phenytoin and amitriptyline are often reported to attenuate pain in chronic conditions. Information on their ability to ameliorate cognitive impairment associated with neuropathic pain remains unclear due to mixed results from studies. This study investigated the effects of phenytoin and amitriptyline on memory deficit associated with neuropathic pain. METHODS: Twenty-eight adult male Wistar rats were randomly divided into four groups: A, B, C, and D (n=7). Groups A, B, C, and D served as sham control, sciatic nerve ligated untreated, sciatic nerve ligated receiving amitriptyline (5 mg/kg), and sciatic nerve ligated receiving phenytoin (10 mg/kg) respectively. Treatments lasted for 14 days, after which both 'Y' maze and novel object recognition test (NOR) were performed. On the last day of treatment, the animals were anesthetized and their brain excised, and the prefrontal cortices and sciatic nerve were processed histologically using hematoxylin and eosin. RESULTS: There was memory impairment in the sciatic nerve ligated untreated group which was statistically significant (p<0.05) when compared to the phenytoin-treated, amitriptyline-treated, and sham control groups using the 'Y' maze and NOR tests. Histological quantification showed that the prefrontal cortices of the ligated animals showed increased neural population in comparison to normal control. These increases were significantly marked in the untreated ligated group. Sciatic nerve of untreated ligated group showed high demyelination and axonal degeneration which was ameliorated in the treated animals. CONCLUSIONS: The administration of amitriptyline and phenytoin can ameliorate neuronal injury, demyelination, and memory impairment associated with neuropathic pain in Wistar rats.

Cannabis-induced Moto-cognitive Dysfunction in Wistar Rats: Ameliorative of Nigella Sativa

Background: Cannabis is a widely used illicit drug with various threats of personality syndrome, and Nigella sativa has been widely implicated as having therapeutic efficacy in many neurological diseases. The present study investigates the ameliorative efficacy of Nigella sativa oil (NSO) on cannabis-induced moto-cognitive defects. Methods: Scopolamine (1 mg/kg i.p.) was given to induce dementia as a standard base line for cannabis (20 mg/kg)-induced cognitive impairment, followed by an oral administration of NSO (1 ml/kg) for 14 consecutive days. The Morris water maze (MWM) paradigm was used to assess the memory index, the elevated plus maze was used for anxiety-like behaviour, and the open field test was used for locomotor activities; thereafter, the rats were sacrificed and their brains were removed for histopathologic studies. Results: Cannabis-like Scopolamine caused memory impairment, delayed latency in the MWM, and anxiety-like behaviour, coupled with alterations in the cerebello-hippocampal neurons. The post-treatment of rats with NSO mitigated cannabis-induced cognitive dysfunction as with scopolamine and impaired anxiety-like behaviour by increasing open arm entry, line crossing, and histological changes. Conclusions: The observed ameliorative effects of NSO make it a promising agent against moto-cognitive dysfunction and cerebelo-hippocampal alterations induced by cannabis.