Specific Brain Sites Research Articles

Acoustically targeted measurement of transgene expression in the brain.

Gene expression is a critical component of brain physiology, but monitoring this expression in the living brain represents a major challenge. Here, we introduce a new paradigm called recovery of markers through insonation (REMIS) for noninvasive measurement of gene expression in the brain with cell type, spatial, and temporal specificity. Our approach relies on engineered protein markers that are produced in neurons but exit into the brain's interstitium. When ultrasound is applied to targeted brain regions, it opens the blood-brain barrier and releases these markers into the bloodstream. Once in blood, the markers can be readily detected using biochemical techniques. REMIS can noninvasively confirm gene delivery and measure endogenous signaling in specific brain sites through a simple insonation and a subsequent blood test. REMIS is reliable and demonstrated consistent improvement in recovery of markers from the brain into the blood. Overall, this work establishes a noninvasive, spatially specific method of monitoring gene delivery and endogenous signaling in the brain.

The expression of parental fear-conditioned memory in the hippocampal neurons of subsequent progeny

This paper researches the concept of parental fear-conditioned memory and its potential transmission to subsequent generations, focusing on examining whether memory traces formed in the hippocampus CA3 region of parents are retained in the hippocampus of their offspring. Through experiments conducted on mice, it is expected that the findings will reveal how fear conditioning in the parental generation impacts the behavioral sensitivity and neuroanatomical changes in the hippocampal neurons of the offspring. The study explores the potential inheritance of transgenerational memory from parents to children and the specific brain sites involved.

Sex-divergent effects of hindbrain GLP-1-producing neuron activation in rats.

Glucagon-like peptide-1 (GLP-1) analogs represent a new class of weight-loss medication, which has recently exponentially grown in popularity. GLP-1 is produced in the intestinal L cells in response to macronutrient intake, but it is also produced in the brain in a subset of neurons in the nucleus of the solitary tract (NTS). Exogenously-delivered GLP-1 analogs reduce food intake and food-motivated behavior in male and female rats, with some sex divergence of these effects in specific brain sites. These analogs potentially target GLP-1 receptors endogenously supplied by the gut and brain-produced GLP-1. The function of the NTS GLP-1-producing neurons [Gcg neurons] is still relatively unknown in rats. Moreover, even less is understood about the function of these neurons in females. We have recently developed a transgenic rat that expresses Cre under the Gcg promoter. Here, we interrogate this new animal model with optogenetics and chemogenetics to determine whether activation of the NTS GLP-1 neurons affects ingestive and motivated behavior in male and female rats. Optogenetic activation of the NTS Gcg neurons robustly reduced chow intake in both male and female rats. Interestingly, motivated behavior for a sucrose reward was reduced exclusively in females. To ensure that this unexpected sex difference was not activation method-specific, we next virally introduced excitatory DREADD receptors into the Gcg neurons and investigated the effect of chemogenetic activation of these neurons on ingestive and motivated behavior. Even upon chemogenetic activation, female rats reduced their motivation to obtain the sucrose reward, yet no effect on this behavior was observed in males. Our results show that activation of hindbrain Gcg neurons is sufficient to reduce food intake in both sexes. In females, but not males, Gcg neuron activation alone is also sufficient to reduce motivated behavior for sucrose. Thus, there is a sex difference in the ability of GLP-1-producing neuron activation to control motivated behavior for food.

Lesion-symptom mapping of language impairments in people with brain tumours: The influence of linguistic stimuli.

People with tumours in specific brain sites might face difficulties in tasks with different linguistic material. Previous lesion-symptom mapping studies (VLSM) demonstrated that people with tumours in posterior temporal regions have more severe linguistic impairments. However, to the best of our knowledge, preoperative performance and lesion location on tasks with different linguistic stimuli have not been examined. In the present study, we performed VLSM on 52 people with left gliomas to examine whether tumour distribution differs depending on the tasks of the Aachen Aphasia Test. The VLSM analysis revealed that single-word production (e.g. object naming) was associated with the inferior parietal lobe and that compound and sentence production were additionally associated with posterior temporal gyri. Word repetition was affected in people with tumours in inferior parietal areas, whereas sentence repetition was the only task to be associated with frontal regions. Subcortically, word and sentence production were found to be affected in people with tumours reaching the arcuate fasciculus, and compound production was primarily associated with tumours affecting the inferior longitudinal and inferior fronto-occipital fasciculus. Our work shows that tasks with linguistic stimuli other than single-word naming (e.g. compound and sentence production) relate to additional cortical and subcortical brain areas. At a clinical level, we show that tasks that target the same processes (e.g. repetition) can have different neural correlates depending on the linguistic stimuli used. Also, we highlight the importance of left temporoparietal areas.

Mind-Body (Hypnotherapy) Treatment of Women With Urgency Urinary Incontinence: Changes in Brain Attentional Networks

(Abstracted from Am J Obstet Gynecol 2021;224:498.e1–498.e10) Involuntary urine loss associated with a sudden sense of urgency, known as urgency urinary incontinence (UUI), affects millions of women and significantly impairs quality of life. Altered perceptual awareness has been theorized to play a role in UUI, with functional magnetic resonance imaging (fMRI) identifying specific brain sites that may function abnormally in these patients.

Angiotensinergic receptors in the medial amygdaloid nucleus differently modulate behavioral responses in the elevated plus-maze and forced swimming test in rats

The brain renin-angiotensin system (RAS) has been implicated in anxiety and depression disorders, but the specific brain sites involved are poorly understood. The medial amygdaloid nucleus (MeA) is involved in expression of behavioral responses. However, despite evidence of the presence of all angiotensinergic receptors in this amygdaloid nucleus, regulation of anxiety- and depressive-like behaviors by angiotensinergic neurotransmissions within the MeA has never been reported. Thus, the present study aimed to investigate the role angiotensin II (AT1 and AT2 receptors) and angiotensin-(1–7) (Mas receptor) receptors present within the MeA in behavioral responses in the elevated plus-maze (EPM) and forced swimming test (FST). For this, male Wistar rats had cannula-guide bilaterally implanted into the MeA, and independent sets of animals received bilateral microinjections of either the selective AT1 receptor antagonist losartan, the selective AT2 receptor antagonist PD123319, the selective Mas receptor antagonist A-779 or vehicle into the MeA before the EPM and FST. Treatment of the MeA with either PD123319 or A-779 decreased the EPM open arms exploration, while losartan did not affect behavioral responses in this apparatus. However, intra-MeA microinjection of losartan decreased immobility in the FST. Administration of either PD123319 or A-779 into the MeA did not affect the immobility during the FST, but changed the pattern of the active behaviors swimming and climbing. Altogether, these results indicate the presence of different angiotensinergic mechanisms within the MeA controlling behavioral responses in the FST and EPM.

Relationship between anxiety and static and dynamic balance disorder in subjects with cerebrovascular accident (stroke) diagnosis.

Background: According to the World Health Organization, cerebrovascular accident (Stroke) is defined as an acute neurological dysfunction that occurs due to a change in the brain circulation, resulting in signs and symptoms that compromise specific brain sites, persisting for more than 24 hours. There is a range of symptoms that stroke causes, in which motor changes become the most evident and feared symptoms by the patient, as they are the causes of several functional limitations, directly interfering with activities of daily living and possibly causing psychological disorders. Anxiety disorder is one of the psychological disorders that the subject after stroke may have. This disorder is characterized as a state of discouragement, distress and fear, which causes a series of symptoms, such as tachycardia, muscle tension, chronic pain, among others. These emotional and physical changes may be beneficial or harmful to the regularization of the disorders that stroke causes. Objective: To analyze the interference of anxiety on the static and dynamic balance of patients diagnosed with stroke. Methods: Fifteen patients with stroke, aged 40 to 80 years, were assessed using the Hospital Anxiety and Depression Scale, Timed Up and Go test for dynamic balance and the Berg Scale for static balance. Data were tabulated in Excel and analyzed using SPSS. Results: Significant values were found for the correlation between anxiety and balance, in which the results analyzed showed that the balance of patients with stroke can be negatively exacerbated due to the anxiety that affects them. Conclusion: It can be concluded from these results that anxiety can alter the balance of stroke patients and thus, it is shown the importance of a multidisciplinary treatment from the first moment to leverage the treatment.

SUN-LB57 Assessing the Requirement of Arcuate Nucleus Kisspeptin Neurons in Puberty Onset and Adult LH Secretion

Puberty is a critical developmental period marking the transition to adulthood and attainment of reproductive capability. A hallmark of puberty is increased pulsatile secretion of pituitary luteinizing hormone (LH) which is itself driven by increased gonadotropin-releasing hormone (GnRH) from the forebrain. The mechanisms governing GnRH neuron activation at puberty still remain unclear, but likely include enhanced stimulation from upstream reproductive neural circuits, including kisspeptin neurons. Kisspeptin is a potent stimulator of GnRH and is required for proper puberty onset. However, the specific brain site(s) from where kisspeptin signaling arises to trigger puberty remain unclarified. Kisspeptin is expressed in two primary nuclei in the hypothalamus, the arcuate nucleus (ARC) and anteroventral periventricular (AVPV) region. Studies suggest that, in adulthood, ARC Kiss1 neurons are involved in driving pulsatile secretion of GnRH (and hence, LH) in both sexes whereas AVPV Kiss1 neurons participate in the preovulatory GnRH/LH surge in females. However, the specific role of either kisspeptin neuron population in puberty onset still remains unknown. We previously showed that both kisspeptin populations show increased Kiss1 gene expression across the pubertal period, yet whether just one or both (or neither) population is needed for puberty to occur has not been determined. Here, we sought to tease out the role—if any—of ARC and AVPV Kiss1 neurons in the pubertal onset process. Since ARC Kiss1 neurons are abundant in both sexes and drive pulsatile GnRH secretion in adulthood, we hypothesized that ARC Kiss1 neurons are necessary for normal puberty onset and, conversely, that AVPV Kiss1 neurons are not sufficient on their own to induce normal puberty. To test this hypothesis, we used a Cre-specific diphtheria toxin approach to ablate just ARC Kiss1 neurons in juvenile mice (~ 2 weeks old) while leaving AVPV Kiss1 neurons intact. Preliminary data thus far indicates that site specific ablation of just ARC Kiss1 neurons during the juvenile period significantly delays puberty onset in both sexes, as measured by vaginal opening, first estrous, and preputial separation. In addition, selective ARC Kiss1 neuron ablation in juvenile life diminishes pulsatile LH secretion levels measured in adulthood, but does not alter LH surge generation in adult females. These preliminary findings empirically demonstrate that, in mice, ARC Kiss1 neurons are required for proper activation of the reproductive axis during puberty but not the LH surge in adulthood, and AVPV Kiss1 neurons are not sufficient to trigger normal pubertal onset.

Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview.

Cannabidiol (CBD) represents a new promising drug due to a wide spectrum of pharmacological actions. In order to relate CBD clinical efficacy to its pharmacological mechanisms of action, we performed a bibliographic search on PUBMED about all clinical studies investigating the use of CBD as a treatment of psychiatric symptoms. Findings to date suggest that (a) CBD may exert antipsychotic effects in schizophrenia mainly through facilitation of endocannabinoid signalling and cannabinoid receptor type 1 antagonism; (b) CBD administration may exhibit acute anxiolytic effects in patients with generalised social anxiety disorder through modification of cerebral blood flow in specific brain sites and serotonin 1A receptor agonism; (c) CBD may reduce withdrawal symptoms and cannabis/tobacco dependence through modulation of endocannabinoid, serotoninergic and glutamatergic systems; (d) the preclinical pro-cognitive effects of CBD still lack significant results in psychiatric disorders. In conclusion, current evidences suggest that CBD has the ability to reduce psychotic, anxiety and withdrawal symptoms by means of several hypothesised pharmacological properties. However, further studies should include larger randomised controlled samples and investigate the impact of CBD on biological measures in order to correlate CBD's clinical effects to potential modifications of neurotransmitters signalling and structural and functional cerebral changes.

Integrated DNA methylation analysis identifies topographical and tumoral biomarkers in pilocytic astrocytomas.

Pilocytic astrocytoma (PA) is the most common glioma in pediatric patients and occurs in different locations. Chromosomal alterations are mostly located at chromosome 7q34 comprising the BRAF oncogene with consequent activation of the mitogen-activated protein kinase pathway. Although genetic and epigenetic alterations characterizing PA from different localizations have been reported, the role of epigenetic alterations in PA development is still not clear. The aim of this study was to investigate whether distinctive methylation patterns may define biologically relevant groups of PAs. Integrated DNA methylation analysis was performed on 20 PAs and 4 normal brain samples by Illumina Infinium HumanMethylation27 BeadChips.We identified distinct methylation profiles characterizing PAs from different locations (infratentorial vs supratentorial) and tumors with onset before and after 3 years of age. These results suggest that PA may be related to the specific brain site where the tumor arises from region-specific cells of origin. We identified and validated in silico the methylation alterations of some CpG islands. Furthermore, we evaluated the expression levels of selected differentially methylated genes and identified two biomarkers, one, IRX2, related to the tumor localization and the other, TOX2, as tumoral biomarker.

ASIC1A in neurons is critical for fear-related behaviors.

Acid-sensing ion channels (ASICs) have been implicated in fear-, addiction- and depression-related behaviors in mice. While these effects have been attributed to ASIC1A in neurons, it has been reported that ASICs may also function in nonneuronal cells. To determine if ASIC1A in neurons is indeed required, we generated neuron-specific knockout (KO) mice with floxed Asic1a alleles disrupted by Cre recombinase driven by the neuron-specific synapsin I promoter (SynAsic1a KO mice). We confirmed that Cre expression occurred in neurons, but not all neurons, and not in nonneuronal cells including astrocytes. Consequent loss of ASIC1A in some but not all neurons was verified by western blotting, immunohistochemistry and electrophysiology. We found ASIC1A was disrupted in fear circuit neurons, and SynAsic1a KO mice exhibited prominent deficits in multiple fear-related behaviors including Pavlovian fear conditioning to cue and context, predator odor-evoked freezing and freezing responses to carbon dioxide inhalation. In contrast, in the nucleus accumbens ASIC1A expression was relatively normal in SynAsic1a KO mice, and consistent with this observation, cocaine conditioned place preference (CPP) was normal. Interestingly, depression-related behavior in the forced swim test, which has been previously linked to ASIC1A in the amygdala, was also normal. Together, these data suggest neurons are an important site of ASIC1A action in fear-related behaviors, whereas other behaviors likely depend on ASIC1A in other neurons or cell types not targeted in SynAsic1a KO mice. These findings highlight the need for further work to discern the roles of ASICs in specific cell types and brain sites.

Targeting the Brain with Nanomedicine.

Herein, we review innovative nanomedicine-based approaches for treating, preventing and diagnosing neurodegenerative diseases. We focus on nanoscale systems such as polymeric nanoparticles (NPs), liposomes, micelles and other vehicles (e.g. dendrimers, nanogels, nanoemulsions and nanosuspensions) for targeted delivery of bioactive molecules to the brain. To ensure maximum selectivity for optimal therapeutic or diagnostic results, researchers must employ delivery systems that are non-toxic, biodegradable and biocompatible. This entails: (i) use of "safe" materials, such as polymers or lipids; (ii) targeting to the brain and, specifically, to the desired active site within the brain; (iii) controlled release of the loaded agent; and (iv) use of agents that, once released into the brain, will exhibit the desired pharmacologic activity. Here, we explore the design and preclinical use of representative delivery systems that have been proposed to date. We then analyze the principal challenges that have delayed clinical application of these and other approaches. Lastly, we look at future developments in this area, addressing the needs for increased penetration of the blood brain barrier (BBB), enhanced targeting of specific brain sites, improved therapeutic efficacy and lower neurotoxicity.

Coherence: The Measurement and Application of Brain Connectivity

While much knowledge has been gained by the endeavor to link specific brain sites with specific cognitive functions, modern conceptualizations of brain activity focus much more on the function of networks of brain regions. A key construct in defining these networks has been the study of connectivity across regions. In this review, we discuss several methods of measuring connectivity and focus primarily on the utility of electroencephalographic (EEG) coherence. While over- and under-connectivity have been related to numerous clinical phenomena, we focus our discussion on the role of connectivity in reading and language disorders, and present a Neurocognitive Connectivity (NCC) framework for understanding these disorders. We argue that EEG coherence presents a unique target for treatment of these and other populations, in that the ability to modulate connectivity via EEG neurofeedback has been shown to be of significant clinical utility.

The Role of VIP in Social Behavior: Neural Hotspots for the Modulation of Affiliation, Aggression, and Parental Care.

Although the modulation of social behaviors by most major neurochemical systems has been explored, there are still standouts, including the study of vasoactive intestinal polypeptide (VIP). VIP is a modulator of circadian, reproductive, and seasonal rhythms and is well known for its role in reproductive behavior, as it is the main vertebrate prolactin-releasing hormone. Originally isolated as a gut peptide, VIP and its cognate receptors are present in virtually every brain area that is important for social behavior, including all nodes of the core "social behavior network" (SBN). Furthermore, VIP cells show increased transcriptional activity throughout the SBN in response to social stimuli. Using a combination of comparative and mechanistic approaches in socially diverse species of estrildid finches and emberizid sparrows, we have identified neural "hotspots" in the SBN that relate to avian affiliative behavior, as well as neural "hotspots" that may represent critical nodes underlying a trade-off between aggression and parental care. Specifically, we have found that: (1) VIP fiber densities and VIP receptor binding in specific brain sites, such as the lateral septum, medial extended amygdala, arcopallium, and medial nidopallium, correlate with species and/or seasonal differences in flocking behavior, and (2) VIP cells and fibers within the anterior hypothalamus-caudocentral septal circuit relate positively to aggression and negatively to parental care while VIP elements in the mediobasal hypothalamus relate negatively to aggression and positively to parental care. Thus, while a given behavior or social context likely activates VIP circuitry throughout the SBN and beyond, key brain sites emerge as potential "hotspots" for the modulation of affiliation, aggression, and parental care.

Near-Infrared Spectroscopy - Electroencephalography-Based Brain-State-Dependent Electrotherapy: A Computational Approach Based on Excitation-Inhibition Balance Hypothesis.

Stroke is the leading cause of severe chronic disability and the second cause of death worldwide with 15 million new cases and 50 million stroke survivors. The poststroke chronic disability may be ameliorated with early neuro rehabilitation where non-invasive brain stimulation (NIBS) techniques can be used as an adjuvant treatment to hasten the effects. However, the heterogeneity in the lesioned brain will require individualized NIBS intervention where innovative neuroimaging technologies of portable electroencephalography (EEG) and functional-near-infrared spectroscopy (fNIRS) can be leveraged for Brain State Dependent Electrotherapy (BSDE). In this hypothesis and theory article, we propose a computational approach based on excitation–inhibition (E–I) balance hypothesis to objectively quantify the poststroke individual brain state using online fNIRS–EEG joint imaging. One of the key events that occurs following Stroke is the imbalance in local E–I (that is the ratio of Glutamate/GABA), which may be targeted with NIBS using a computational pipeline that includes individual “forward models” to predict current flow patterns through the lesioned brain or brain target region. The current flow will polarize the neurons, which can be captured with E–I-based brain models. Furthermore, E–I balance hypothesis can be used to find the consequences of cellular polarization on neuronal information processing, which can then be implicated in changes in function. We first review the evidence that shows how this local imbalance between E–I leading to functional dysfunction can be restored in targeted sites with NIBS (motor cortex and somatosensory cortex) resulting in large-scale plastic reorganization over the cortex, and probably facilitating recovery of functions. Second, we show evidence how BSDE based on E–I balance hypothesis may target a specific brain site or network as an adjuvant treatment. Hence, computational neural mass model-based integration of neurostimulation with online neuroimaging systems may provide less ambiguous, robust optimization of NIBS, and its application in neurological conditions and disorders across individual patients.

Antagonism of V1b receptors promotes maternal motivation to retrieve pups in the MPOA and impairs pup-directed behavior during maternal defense in the mpBNST of lactating rats

Recent studies using V1b receptor (V1bR) knockout mice or central pharmacological manipulations in lactating rats highlighted the influence of this receptor for maternal behavior. However, its role in specific brain sites known to be important for maternal behavior has not been investigated to date. In the present study, we reveal that V1bR mRNA (qPCR) and protein levels (Western blot) within either the medial preoptic area (MPOA) or the medial-posterior part of the bed nucleus of the stria terminalis (mpBNST) did not differ between virgin and lactating rats. Furthermore, we characterized the effects of V1bR blockade via bilateral injections of the receptor subtype-specific antagonist SSR149415 within the MPOA or the mpBNST on maternal behavior (maternal care under non-stress and stress conditions, maternal motivation to retrieve pups in a novel environment, maternal aggression) and anxiety-related behavior in lactating rats. Blocking V1bR within the MPOA increased pup retrieval, whereas within the mpBNST it decreased pup-directed behavior, specifically licking/grooming the pups, during the maternal defense test. In addition, immediately after termination of the maternal defense test, V1bR antagonism in both brain regions reduced nursing, particularly arched back nursing. Anxiety-related behavior was not affected by V1bR antagonism in either brain region. In conclusion our data indicate that V1bR antagonism significantly modulates different aspects of maternal behavior in a brain region-dependent manner.

Whole Mouse Brain Image Reconstruction from Serial Coronal Sections Using FIJI (ImageJ).

Whole-brain reconstruction of the mouse enables comprehensive analysis of the distribution of neurochemical markers, the distribution of anterogradely labeled axonal projections or retrogradely labeled neurons projecting to a specific brain site, or the distribution of neurons displaying activity-related markers in behavioral paradigms. This unit describes a method to produce whole-brain reconstruction image sets from coronal brain sections with up to four fluorescent markers using the freely available image-processing program FIJI (ImageJ).

Focused ultrasound-enhanced intranasal delivery of brain-derived neurotrophic factor

The therapeutic use of neurotrophic factors in the treatment of central nervous system diseases has been restrained by their low blood-barrier permeability and rapid degradation in the blood. Intranasal (IN) administration is a promising approach for delivering neurotrophic factors directly to the brain, bypassing the BBB. However, IN delivery has low efficiency and does not offer localized delivery to specific brain sites. The objective of this study was to demonstrate the feasibility of FUS-enhanced IN delivery of brain derived neurotrophic factor (BDNF) at a targeted location. BDNF was administered through IN route in wild-type mice (n = 7) followed by FUS sonication at the left caudaputamen in the presence of systemically circulating microbubbles. The contralateral right caudaputamen was used as control for IN delivery only. Immunohistochemistry staining was used to assess the distribution of BDNF and the bioactivity of BDNF in activating the downstream signaling. It was found that FUS enhanced the delivery efficiency of IN administered BDNF at the targeted region, where BDNF penetrated deep into the brain tissue instead of confining within the perivascular spaces as in the contralateral control side. Furthermore, the delivered BDNF reached sufficient concentration to activate the downstream signaling pathway.

Genetic influences on resting-state functional networks: A twin study.

Alterations in resting-state networks (RSNs) are often associated with psychiatric and neurologic disorders. Given this critical linkage, it has been hypothesized that RSNs can potentially be used as endophenotypes for brain diseases. To validate this notion, a critical step is to show that RSNs exhibit heritability. However, the investigation of the genetic basis of RSNs has only been attempted in the default-mode network at the region-of-interest level, while the genetic control on other RSNs has not been determined yet. Here, we examined the genetic and environmental influences on eight well-characterized RSNs using a twin design. Resting-state functional magnetic resonance imaging data in 56 pairs of twins were collected. The genetic and environmental effects on each RSN were estimated by fitting the functional connectivity covariance of each voxel in the RSN to the classic ACE twin model. The data showed that although environmental effects accounted for the majority of variance in wide-spread areas, there were specific brain sites that showed significant genetic control for individual RSNs. These results suggest that part of the human brain functional connectome is shaped by genomic constraints. Importantly, this information can be useful for bridging genetic analysis and network-level assessment of brain disorders.

Brain Targeting Drug Delivery System: A Review

The Overall prevalence rate for CNS pathology has demonstrated that approximately 1.5 billion people under going from disorders of central nervous system. The most distressing fact about delivery of drugs to the CNS is the presence of blood brain barrier that have a tendency to impair the drug distribution and denotes the major impediment for the development of CNS drugs. Neuropeptides and many drugs which are hydrophilic in nature, possibly will encompass the intricacy while passing the blood brain barrier. The net amount of delivered drug (medicinal agent) and its capability to gain access to the pertinent target sites are the main considering points for CNS drug development. In order to distribute the drugs into the CNS via passing the blood brain barrier, many new emerging approaches have been developed for example Magnetic drug targeting, chemical delivery Systems, Drug carrier systems (antibodies, liposomes or Nanoparticles). Among drug carrier system, Nanoparticles exhibit an impressive attention in the field of targeted drug delivery system because of possessing solid colloidal particles with a size range between 1-lOOOnm. Gradual drug release reduced peripheral toxicity and potential totarget specific brain sites by crossing the blood brain barrier are major benefits contributed by Nanoparticles. In this review we will discuss the methodologies for targeting the brain site.