Impairment of entorhinal cortex network activity in Alzheimer's disease.

The entorhinal cortex (EC) stands out as a critical brain region affected in the early phases of Alzheimer's disease (AD), with some of the disease's pathological processes originating from this area, making it one of the most crucial brain regions in AD. Recent research highlights disruptions in the brain's network activity, characterized by heightened excitability and irregular oscillations, may contribute to cognitive impairment. These disruptions are proposed not only as potential therapeutic targets but also as early biomarkers for AD. In this paper, we will begin with a review of the anatomy and function of EC, highlighting its selective vulnerability in AD. Subsequently, we will discuss the disruption of EC network activity, exploring changes in excitability and neuronal oscillations in this region during AD and hypothesize that, considering the advancements in neuromodulation techniques, addressing the disturbances in the network activity of the EC could offer fresh insights for both the diagnosis and treatment of AD.

Investigating the Serotonergic Modulation of Orientation Tuning of Neurons in Primary Visual Cortex of Anesthetized Mice.

Introduction: Sensory processing is profoundly regulated by brain neuromodulatory systems. One of the main neuromodulators is serotonin which influences higher cognitive functions, such as different aspects of perceptual processing. Accordingly, malfunction in the serotonergic system may lead to visual illusion in psychiatric disorders, such as autism and schizophrenia. This study aims to investigate the serotonergic modulation of visual responses of neurons to stimulus orientation in the primary visual cortex. Methods: Eight-week-old naive mice were anesthetized and a craniotomy was done on the region of interest in the primary visual cortex. Spontaneous and visual-evoked activities of neurons were recorded before and during the electrical stimulation of the dorsal raphe nucleus using in vivo whole-cell patch-clamp recording. The square-wave grating of 12 orientations was presented. The data were analyzed and the Wilcoxon signed-rank test was used to compare the data of two conditions that belong to the same neurons, with or without electrical stimulation. Results: The serotonergic system changed the orientation tuning of nearly 60% of recorded neurons by decreasing the mean firing rate in two independent visual response components, namely gain and baseline response. It also increased the mean firing rate in a small number of neurons (about 20%). Additionally, it left the preferred orientation and sensitivity of neurons unchanged. Conclusion: Serotonergic modulation showed a bidirectional effect. It causes predominately divisive and subtractive decreases in the visual responses of the neurons in the primary visual cortex that can modify the balance between internal and external sensory signals and result in disorders. Highlights: The serotonergic system predominantly decreased the mean firing rate of neurons in the primary visual cortex.The serotonergic system decreased responses of visual cortical neurons by subtractive and divisive changes of orientation tuning.The serotonergic system leaves the spontaneous activity of visual cortical neurons unchanged. Plain Language Summary: Serotonin is one of the well-known neuromodulators involved in many physiological functions of the brain, such as sensory processing. It can play an essential role in producing perceptual psychotic episodes following the use of psychedelic drugs. Neural mechanisms of changes in cortical processing by the serotonergic system are not elucidated enough. In this study, we showed the electrical stimulation of the dorsal raphe nucleus as the main resource for projecting serotonergic neurons to the visual cortex, causing to decrease in visual-evoked responses of neurons in the primary visual cortex without changing the spontaneous activity. This effect may lead to an imbalance between the brain's intrinsic and stimulus-evoked activity and result in various kinds of psychiatric disorders, such as visual hallucinogenic experiences in schizophrenia and autism. Accordingly, it is crucial to understand the mechanisms by which serotonin affects the rapid and long-term activity of neocortical circuits. Such studies can be helpful in the diagnosis and treatment of disorders related to the neuromodulatory roles of the serotonergic system by providing new methods for rebalancing these intricate components.

Effects of optogenetic and visual stimulation on gamma activity in the visual cortex.

Studying brain functions and activity during gamma oscillations can be a challenge because it requires careful planning to create the necessary conditions for a controlled experiment. Such an experiment consists of placing the brain into a gamma state and investigating cognitive processing with a careful design. Cortical oscillations in the gamma frequency range (30-80 Hz) play an essential role in a variety of cognitive processes, including visual processing and cognition. The present study aims to investigate the effects of a visual stimulus on the primary visual cortex under gamma oscillations. Specifically, we sought to explore the behavior of gamma oscillations triggered by optogenetic stimulation in the II and IV layers of the visual cortex, both with and without concurrent visual stimulation. Our results show that optogenetic stimulation increases the power of gamma oscillation in both layers of the visual cortex. However, the combined stimuli resulted in a reduction of gamma power in layer II and an increase and reinforcement in gamma power in layer IV. Modelling the results with the Wilson-Cowan model suggests changes in the input of the excitatory population due to the combined stimuli. In addition, our analysis of the data using the Lempel-Ziv complexity method supports our interpretations from the modeling. Thus, our results suggest that optogenetic stimulation enhances low gamma power in both layers of the visual cortex, while simultaneous visual stimulation has differing effects on the two layers, reducing gamma power in layer II and increasing it in layer IV.

Inhibitory Effects of Dutasteride on TLR4: An In vitro Pain Study.

Dutasteride was potentially proposed to control chronic pain by Toll-Like Receptor 4 (TLR4) inhibition through its effect on TLR4 expression, Myeloid differentiation primary response 88 (MyD88), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), secretory Interleukin-1ß (IL-1ß), and nitric oxide (NO) in the Lipopolysaccharides (LPS)-stimulated U-87 MG cell line. Human astrocytoma U-87 MG cell line was cultured and incubated with 10 µg/mL of LPS for 24 hours to create a neuro-inflammation model, using two different treatment approaches. The first approach included LPS treatment for 24 hours, followed by dutasteride (20 µg/mL) incubation for the next 72 hours. In the second treatment approach, the cells were co-incubated with LPS and dutasteride for 72 hours. Expression of TLR4, MyD88, NF-κBp65, and secretory IL-1 was evaluated by Western blotting while expression of NO was assessed by NO assay. TLR4, MyD88, NF-κBp65, and secretory IL-1ß levels increased in LPS-treated cells after 24 hours. Dutasteride significantly decreased the secretion of NO and also, the levels of TLR4, MyD88, and NF-κBp65 in both treatment approaches. No difference in IL-1ß level was seen with the second treatment approach. Dutasteride has anti-inflammatory properties and probably analgesic effects, by mechanisms different from conventional analgesics.

The promoting effect of vagus nerve stimulation on Lempel-Ziv complexity index of consciousness.

Recent studies suggest that vagus nerve stimulation (VNS) promotes cognitive and behavioral restoration after traumatic brain injuries. As vagus nerve has wide effects over the brain and visceral organs, stimulation of the sensory/visceral afferents might have a therapeutic potential to modulate the level of consciousness. One of the most important challenges in studying consciousness is objective evaluation of the consciousness level. Brain complexity that can be measured through Lempel-Ziv complexity (LZC) index was used as a novel mathematical approach for objective measurement of consciousness. The main goal of our study was to examine the effects of VNS on LZC index of consciousness. In this study, we did VNS on the anesthetized rats, and simultaneously LFPs recording was performed in two different cortical areas of primary somatosensory (S1) or visual (V1) cortex. LZC and the amplitude of slow waves were computed during different periods of VNS. We found that the LZC index during VNS period was significantly higher in both of the cortical areas of S1 and V1. Slow-wave activity decreased during VNS in S1, while there was no significant change in V1. Our findings showed that VNS can augment the consciousness level, and LZC index is a more sensitive parameter for detecting the level of consciousness.

The application of EEG power for the prediction and interpretation of consumer decision-making: A neuromarketing study.

The application of biometric data has been the center of attention for neuromarketing researches. Understanding the underlying mechanisms behind consumer shopping behaviors and the way that advertising affects such behavior are the most important issues that need more investigations. In this study, two purposes were focused including (1)the potential of EEG spectral power for prediction of consumers' preferences and (2)interpretation of the alteration of consumers' decision-making in shopping behavior when the content of an advertisement including background color and promotions was changed. For this purpose, advertisements related to different mobile phone brands which were different according to the content were shown to the participants followed by EEG (electroencephalography) recording. The power of the EEG data was used for finding the most important brain regions for distinguishing between preferences and predicting the incidence of decision-making. Furthermore, the results were used for interpretation of the observed participant behavior. The obtained results showed that the extracted features from EEG power could predict consumer's decision-making incidence with relatively high accuracy (>87%) and distinguished between "Like" and "Dislike" preferences with accuracy higher than 63%. Also, the most discriminative channels for predicting the incidence of decision-making about liking/disliking or buying a product were found to be frontal and Centro-parietal locations (Fp1, Cp3, Cpz) while the difference between "Like" and "Dislike" decisions was observed mostly in the frontal electrodes (F4 and Ft8). Furthermore, the results showed that adding the background color to the designed advertisement had a negative impact on the degree of liking a product. In conclusion, EEG data analysis can be used as a useful tool for predicting costumer decision-making, while in order to obtain higher accuracies, other features should be tested for distinguishing between different preferences.

Electrophysiological Profiling of Neocortical Neural Subtypes: A Semi-Supervised Method Applied to in vivo Whole-Cell Patch-Clamp Data.

A lot of efforts have been made to understand the structure and function of neocortical circuits. In fact, a promising way to understand the functions of cortical circuits is the classification of the neural types, based on their different properties. Recent studies focused on applying modern computational methods to classify neurons based on molecular, morphological, physiological, or mixed of these criteria. Although there are studies in the literature on in vitro/vivo extracellular or in vitro intracellular recordings, a study on the classification of neuronal types using in vivo whole-cell patch-clamp recordings is still lacking. We thus proposed a novel semi-supervised classification method based on waveform shape of neurons' spikes using in vivo whole-cell patch-clamp recordings. We, first, detected spike candidates. Then discriminative features were extracted from the time samples of the spikes using discrete cosine transform. We then extracted the center of clusters using fuzzy c-mean clustering and finally, the neurons were classified using the minimum distance classifier. We distinguished three types of neurons: excitatory pyramidal cells (Pyr) and two types of inhibitory neurons: GABAergic- parvalbumin positive (PV), and somatostatin positive (SST) non-pyramidal cells in layer II/III of the mice primary visual cortex. We used 10-fold cross validation in our study. The classification accuracy for PV, Pyr, and SST was 91.59 ± 1.69, 97.47 ± 0.67, and 89.06 ± 1.99, respectively. Overall, the algorithm correctly classified 92.67 ± 0.54% of the cells, confirming the relative robustness of the discriminant functions. The performance of the method was further assessed on in vitro recordings by using a pool of 50 neurons from Allen institute Cell Types Database (5 major subtypes of neurons: Pyr, PV, SST, 5HT3a, and vasoactive intestinal peptide (VIP) cells). Its overall accuracy was 84.13 ± 0.81% on this data set using cross validation framework. The proposed algorithm is thus a promising new tool in recognizing cell's type with high accuracy in laboratories using in vivo/vitro whole-cell patch-clamp recording technique. The developed programs and the entire dataset are available online to interested readers.

Parvalbumin-expressing interneurons can act solo while somatostatin-expressing interneurons act in chorus in most cases on cortical pyramidal cells.

Neural circuits in the cerebral cortex consist primarily of excitatory pyramidal (Pyr) cells and inhibitory interneurons. Interneurons are divided into several subtypes, in which the two major groups are those expressing parvalbumin (PV) or somatostatin (SOM). These subtypes of interneurons are reported to play distinct roles in tuning and/or gain of visual response of pyramidal cells in the visual cortex. It remains unclear whether there is any quantitative and functional difference between the PV → Pyr and SOM → Pyr connections. We compared unitary inhibitory postsynaptic currents (uIPSCs) evoked by electrophysiological activation of single presynaptic interneurons with population IPSCs evoked by photo-activation of a mass of interneurons in vivo and in vitro in transgenic mice in which PV or SOM neurons expressed channelrhodopsin-2, and found that at least about 14 PV neurons made strong connections with a postsynaptic Pyr cell while a much larger number of SOM neurons made weak connections. Activation or suppression of single PV neurons modified visual responses of postsynaptic Pyr cells in 6 of 7 pairs whereas that of single SOM neurons showed no significant modification in 8 of 11 pairs, suggesting that PV neurons can act solo whereas most of SOM neurons may act in chorus on Pyr cells.

Curtailing effect of awakening on visual responses of cortical neurons by cholinergic activation of inhibitory circuits.

Visual responsiveness of cortical neurons changes depending on the brain state. Neural circuit mechanism underlying this change is unclear. By applying the method of in vivo two-photon functional calcium imaging to transgenic rats in which GABAergic neurons express fluorescent protein, we analyzed changes in visual response properties of cortical neurons when animals became awakened from anesthesia. In the awake state, the magnitude and reliability of visual responses of GABAergic neurons increased whereas the decay of responses of excitatory neurons became faster. To test whether the basal forebrain (BF) cholinergic projection is involved in these changes, we analyzed effects of electrical and optogenetic activation of BF on visual responses of mouse cortical neurons with in vivo imaging and whole-cell recordings. Electrical BF stimulation in anesthetized animals induced the same direction of changes in visual responses of both groups of neurons as awakening. Optogenetic activation increased the frequency of visually evoked action potentials in GABAergic neurons but induced the delayed hyperpolarization that ceased the late generation of action potentials in excitatory neurons. Pharmacological analysis in slice preparations revealed that photoactivation-induced depolarization of layer 1 GABAergic neurons was blocked by a nicotinic receptor antagonist, whereas non-fast-spiking layer 2/3 GABAergic neurons was blocked only by the application of both nicotinic and muscarinic receptor antagonists. These results suggest that the effect of awakening is mediated mainly through nicotinic activation of layer 1 GABAergic neurons and mixed nicotinic/muscarinic activation of layer 2/3 non-fast-spiking GABAergic neurons, which together curtails the visual responses of excitatory neurons.

Reversal of prenatal morphine exposure-induced memory deficit in male but not female rats.

Impaired memory performance in offspring is one of the long-lasting neurobehavioral consequences of prenatal opiate exposure. Here, we studied the effects of prenatal morphine exposure on inhibitory avoidance memory performance in male and female offspring and also investigated whether these deficits are reversible during the postnatal development. Pregnant Wistar rats received morphine sulfate through drinking water, from the first day of gestation up to the day 13, M1₋13, or to the time of delivery, M1₋21. Four- and ten-week-old (adolescent and adult, respectively) male and female offspring were subjected to behavioral assays and then analysis of proteins involved in apoptosis or in synaptic plasticity. Results revealed that adolescent and adult female rats failed in passive avoidance retention task in both M1₋13 and M1₋21 groups. Adolescent and adult male offspring were similar to control animals in M1₋13 group. However M1₋21 impaired retention task in prepubertal male offspring, and this memory loss was repaired in postpubertal stage. Consistently, Bax/Bcl-2 ratio and cleaved caspase-3 were significantly increased in both M1₋13 and M1₋21 adolescent and adult female rats, but only in M1₋21 adolescent male rats. Furthermore, prenatal morphine exposure reduced the expression of brain-derived neurotrophic factor precursor protein in adolescent and adult female offspring and also decreased p-ca(2+)/calmodulin-dependent kinase II/ca(2+)/calmodulin-dependent kinase II ratio in adolescent male and female rats. Altogether, the results show that prenatal morphine exposure, depending on the time or duration of exposure, has distinct effects on male and female rats, and postnatal development may reverse these deficits more likely in males.

Cell type-specific, presynaptic LTP of inhibitory synapses on fast-spiking GABAergic neurons in the mouse visual cortex.

Properties and plasticity of inhibitory synapses on fast-spiking (FS) GABAergic (FS-GABA) interneurons in layer II/III of the mouse visual cortex were examined in cortical slices by whole-cell recordings of IPSCs or IPSPs evoked by activation of presynaptic FS or non-FS GABAergic interneurons. Unitary IPSCs (uIPSCs) evoked by action potentials of FS-GABA neurons have shorter onset latency, faster rising slope, higher peak amplitude, and faster decay time than those evoked by action potentials of non-FS-GABA neurons. Tetanic activation of presynaptic FS-GABA neurons induced long-term potentiation (LTP) of uIPSCs, whereas that of presynaptic non-FS-GABA neurons did not induce LTP, indicating that long-term plasticity of inhibitory synapses on FS-GABA neurons is pathway specific. For further analysis of inhibitory synaptic plasticity, IPSPs evoked by electrical stimulation of an adjacent site in the cortex were recorded from FS-GABA neurons. Theta burst stimulation induced LTP of IPSPs in 12 of 14 FS-GABA neurons. The paired-pulse stimulation protocol and coefficient of variation analysis indicated that this form of LTP may be presynaptic in origin. Filling postsynaptic cells with a Ca(2+) chelator did not block the induction of LTP, suggesting no involvement of postsynaptic Ca(2+) rise. Also, this form of LTP was dependent neither on metabotropic glutamate receptors nor voltage-gated Ca(2+) channels of the L and T types. Further pharmacological analysis indicated that voltage-gated Ca(2+) channels other than the P/Q type, such as N and R types, were not involved in LTP, suggesting that P/Q-type channels are a candidate for factors inducing LTP of inhibitory synapses between FS-GABA neurons.

Chemical stimulation of the lateral hypothalamus induces conditioned place preference in rats: Involvement of OX1 and CB1 receptors in the ventral tegmental area.

Orexinergic projection originated from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) has an important role in the acquisition of morphine conditioned place preference (CPP). However, little if any is known about the function and/or effect of orexin on CPP in rats. In the present study, we investigated the direct effect of orexinergic neurons on acquisition of CPP by chemical stimulation of LH and involvement of orexin-A and CB1 receptors within the VTA in development of reward-related behaviors. 129 adult male albino Wistar rats weighing 220-320 g were unilaterally implanted by two separate cannulae into the LH and VTA. The CPP paradigm was done; conditioning score and locomotor activity were recorded by Ethovision software. The results showed that unilateral intra-LH administration of carbachol (62.5, 125 and 250 nmol/0.5 µl saline) as a cholinergic agonist, during conditioning phase, induced CPP in a dose-dependent manner. The maximal effect was shown at the dose of 250 nmol (P<0.001) compared to vehicle (saline) group. However, intra-VTA administration of SB334867 as a selective orexin-A receptor antagonist (0.1, 1 and 10 nmol/0.3 µl DMSO) and AM251 (5, 25 and 125 nmol/0.3 µl DMSO) as a CB1 receptor antagonist, just 5 min before carbachol during the 3-day conditioning phase, could dose-dependently inhibit the development of LH stimulation-induced CPP in the rats. It is supposed that the orexinergic projection from LH to VTA is involved in LH chemical stimulation-induced CPP and orexin-A receptor in the VTA has a substantial role in this phenomenon. Our findings also suggest the existence of cross-talk between cannabinoid and orexinergic systems within the VTA in conditioned place preference paradigm.

Effect of lidocaine administration at the nucleus locus coeruleus level on lateral hypothalamus-induced antinociception in the rat.

Several lines of evidence have shown that stimulation or inactivation of lateral hypothalamus (LH) produces antinociception. In this study, we assessed the role of nucleus locus coeruleus (LC) in antinociceptive response induced by LH stimulation or inactivation in the rat. The cholinergic agonist carbachol (125 nmol/0.5 microl saline) or lidocaine (2%; 0.5 microl) was unilaterally microinjected into the LH with the LC inactivation concurrently. Antinociceptive responses were obtained by tail-flick test and represented as maximal possible effect (MPE) at 5, 10, 15, 20, 30 and 60 min after drug administration. The results showed that microinjection of carbachol into the LH significantly induced antinociception at 5 and 10 min (p<0.001). This effect was significantly blocked by microinjection of lidocaine into the LC. On the other hand, microinjection of lidocaine into LH-induced antinociception at 5 (p<0.01) and 10 (p<0.05) min after administration. However, inactivation of the LC following the LH inactivation increased MPE at 5 min after injection. These findings support the conclusion that antinociception produced by LH stimulation or inactivation involves two separate mechanisms. It seems that analgesic response induced by LH stimulation is mediated in part by the subsequent activation of spinally projecting noradrenergic neurons in the LC cell group.