Prenatal Choline Supplementation Diminishes Early-Life Iron Deficiency-Induced Reprogramming of Molecular Networks Associated with Behavioral Abnormalities in the Adult Rat Hippocampus.

BACKGROUND: Early-life iron deficiency is a common nutrient deficiency worldwide. Maternal iron deficiency increases the risk of schizophrenia and autism in the offspring. Postnatal iron deficiency in young children results in cognitive and socioemotional abnormalities in adulthood despite iron treatment. The rat model of diet-induced fetal-neonatal iron deficiency recapitulates the observed neurobehavioral deficits. OBJECTIVES: We sought to establish molecular underpinnings for the persistent psychopathologic effects of early-life iron deficiency by determining whether it permanently reprograms the hippocampal transcriptome. We also assessed the effects of maternal dietary choline supplementation on the offspring's hippocampal transcriptome to identify pathways through which choline mitigates the emergence of long-term cognitive deficits. METHODS: Male rat pups were made iron deficient (ID) by providing pregnant and nursing dams an ID diet (4 g Fe/kg) from gestational day (G) 2 through postnatal day (PND) 7 and an iron-sufficient (IS) diet (200 g Fe/kg) thereafter. Control pups were provided IS diet throughout. Choline (5 g/kg) was given to half the pregnant dams in each group from G11 to G18. PND65 hippocampal transcriptomes were assayed by next generation sequencing (NGS) and analyzed with the use of knowledge-based Ingenuity Pathway Analysis. Real-time polymerase chain reaction was performed to validate a subset of altered genes. RESULTS: Formerly ID rats had altered hippocampal expression of 619 from >10,000 gene loci sequenced by NGS, many of which map onto molecular networks implicated in psychological disorders, including anxiety, autism, and schizophrenia. There were significant interactions between iron status and prenatal choline treatment in influencing gene expression. Choline supplementation reduced the effects of iron deficiency, including those on gene networks associated with autism and schizophrenia. CONCLUSIONS: Fetal-neonatal iron deficiency reprograms molecular networks associated with the pathogenesis of neurologic and psychological disorders in adult rats. The positive response to prenatal choline represents a potential adjunctive therapeutic supplement to the high-risk group.

Iron deficiency with or without anemia impairs prepulse inhibition of the startle reflex.

Iron deficiency (ID) during early life causes long-lasting detrimental cognitive sequelae, many of which are linked to alterations in hippocampus function, dopamine synthesis, and the modulation of dopaminergic circuitry by the hippocampus. These same features have been implicated in the origins of schizophrenia, a neuropsychiatric disorder with significant cognitive impairments. Deficits in sensorimotor gating represent a reliable endophenotype of schizophrenia that can be measured by prepulse inhibition (PPI) of the acoustic startle reflex. Using two rodent model systems, we investigated the influence of early-life ID on PPI in adulthood. To isolate the role of hippocampal iron in PPI, our mouse model utilized a timed (embryonic day 18.5), hippocampus-specific knockout of Slc11a2, a gene coding an important regulator of cellular iron uptake, the divalent metal transport type 1 protein (DMT-1). Our second model used a classic rat dietary-based global ID during gestation, a condition that closely mimics human gestational ID anemia (IDA). Both models exhibited impaired PPI in adulthood. Furthermore, our DMT-1 knockout model displayed reduced long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), electrophysiological results consistent with previous findings in the IDA rat model. These results, in combination with previous findings demonstrating impaired hippocampus functioning and altered dopaminergic and glutamatergic neurotransmission, suggest that iron availability within the hippocampus is critical for the neurodevelopmental processes underlying sensorimotor gating. Ultimately, evidence of reduced PPI in both of our models may offer insights into the roles of fetal ID and the hippocampus in the pathophysiology of schizophrenia.

Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system.

Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may, therefore, represent a strategy to minimize iatrogenic effects on brain reward circuits.

Dopamine-Evoked Synaptic Regulation in the Nucleus Accumbens Requires Astrocyte Activity.

Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson's disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.

Sociality deficits in serine racemase knockout mice.

BACKGROUND: Studies of schizophrenia have pointed to the role of glutamate in its pathophysiology. Mice lacking D-serine show impairments in neurotransmission through NMDA receptors and display behaviors consistent with features of schizophrenia. Yet, socio-communicative deficits, a characteristic of schizophrenia, have not been reported in serine racemase knockout mice. METHODS: We use behavioral testing (the three-chambered social approach task, the dyadic interaction task, and the novel object recognition task) to examine socio-communicative behaviors in these mice. RESULTS: Serine racemase mice show abnormal social investigation and approach behavior, and differ from wild-type controls in the duration and number of vocalizations they emit in the presence of a conspecific. Serine racemase knockout mice were not impaired in a cognitive test (novel object recognition), although they displayed abnormal behavior in the acquisition phase of the task. CONCLUSIONS: Serine racemase knockout mice demonstrate abnormalities in socio-communicative behaviors consistent with an impairment in sociality, a negative symptom of schizophrenia.

Nucleus Accumbens Fast-Spiking Interneurons Constrain Impulsive Action.

BACKGROUND: The nucleus accumbens (NAc) controls multiple facets of impulsivity but is a heterogeneous brain region with diverse microcircuitry. Prior literature links impulsive behavior in rodents to gamma-aminobutyric acid signaling in the NAc. Here, we studied the regulation of impulsive behavior by fast-spiking interneurons (FSIs), a strong source of gamma-aminobutyric acid-mediated synaptic inhibition in the NAc. METHODS: Male and female transgenic mice expressing Cre recombinase in FSIs allowed us to identify these sparsely distributed cells in the NAc. We used a 5-choice serial reaction time task to measure both impulsive action and sustained attention. During the 5-choice serial reaction time task, we monitored FSI activity with fiber photometry calcium imaging and manipulated FSI activity with chemogenetic and optogenetic methodology. We used electrophysiology, optogenetics, and fluorescent in situ hybridization to confirm these methods were robust and specific to FSIs. RESULTS: In mice performing the 5-choice serial reaction time task, NAc FSIs showed sustained activity on trials ending with correct responses, but FSI activity declined over time on trials ending with premature responses. The number of premature responses increased significantly after sustained chemogenetic inhibition or temporally delimited optogenetic inhibition of NAc FSIs, without any changes in response latencies or general locomotor activity. CONCLUSIONS: These experiments provide strong evidence that NAc FSIs constrain impulsive actions, most likely through gamma-aminobutyric acid-mediated synaptic inhibition of medium spiny projection neurons. Our findings may provide insight into the pathophysiology of disorders associated with impulsivity and may inform the development of circuit-based therapeutic interventions.

Oxytocin enhances observational fear in mice.

Empathy is fundamental to human relations, but its neural substrates remain largely unknown. Here we characterize the involvement of oxytocin in the capacity of mice to display emotional state-matching, an empathy-like behavior. When exposed to a familiar conspecific demonstrator in distress, an observer mouse becomes fearful, as indicated by a tendency to freeze and subsequent efforts to escape. Both intranasal oxytocin administration and chemogenetic stimulation of oxytocin neurons render males sensitive to the distress of an unfamiliar mouse. Acute intranasal oxytocin penetrates the brain and enhances cellular activity within the anterior cingulate cortex, whereas chronic administration produces long-term facilitation of observational fear and downregulates oxytocin receptor expression in the amygdala. None of these manipulations affect fear acquired as a result of direct experience with the stressor. Hence, these results implicate oxytocin in observational fear in mice (rather than fear itself) and provide new avenues for examining the neural substrates of empathy.

Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration.

To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII) in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not reveal any differences in immobility between mutants and controls. In the Elevated Plus Maze, BMPRII mutants and Smad4 mutants showed reduced anxiety, while in exploratory tests, BMPRII mutants showed more interest in object exploration. These results suggest that loss of BMPRII in the mouse hippocampus and forebrain does not disrupt spatial learning and memory encoding, but instead impacts exploratory and anxiety-related behaviors.

Motor cortex stimulation: functional magnetic resonance imaging-localized treatment for three sources of intractable facial pain.

Neuropathic facial pain can be a debilitating condition characterized by stabbing, burning, dysesthetic sensation. With a large range of causes and types, including deafferentation, postherpetic, atypical, and idiopathic, both medicine and neurosurgery have struggled to find effective treatments that address this broad spectrum of facial pain. The authors report the use of motor cortex stimulation to alleviate 3 distinct conditions associated with intractable facial pain: trigeminal deafferentation pain following rhizotomy, deafferentation pain secondary to meningioma, and postherpetic neuralgia. Functional MR imaging was used to localize facial areas on the precentral gyrus prior to surgery. All 3 patients experienced long-lasting complete or near-complete resolution of pain following electrode implantation. Efficacy in pain reduction was achieved through variation of stimulation settings over the course of treatment, and it was assessed using the visual analog scale and narrative report. Surgical complications included moderate postsurgical incisional pain, transient cerebral edema, and intraoperative seizure. The authors' results affirm the efficacy and broaden the application of motor cortex stimulation to several forms of intractable facial pain.

Continuous three-dimensional control of a virtual helicopter using a motor imagery based brain-computer interface.

Brain-computer interfaces (BCIs) allow a user to interact with a computer system using thought. However, only recently have devices capable of providing sophisticated multi-dimensional control been achieved non-invasively. A major goal for non-invasive BCI systems has been to provide continuous, intuitive, and accurate control, while retaining a high level of user autonomy. By employing electroencephalography (EEG) to record and decode sensorimotor rhythms (SMRs) induced from motor imaginations, a consistent, user-specific control signal may be characterized. Utilizing a novel method of interactive and continuous control, we trained three normal subjects to modulate their SMRs to achieve three-dimensional movement of a virtual helicopter that is fast, accurate, and continuous. In this system, the virtual helicopter's forward-backward translation and elevation controls were actuated through the modulation of sensorimotor rhythms that were converted to forces applied to the virtual helicopter at every simulation time step, and the helicopter's angle of left or right rotation was linearly mapped, with higher resolution, from sensorimotor rhythms associated with other motor imaginations. These different resolutions of control allow for interplay between general intent actuation and fine control as is seen in the gross and fine movements of the arm and hand. Subjects controlled the helicopter with the goal of flying through rings (targets) randomly positioned and oriented in a three-dimensional space. The subjects flew through rings continuously, acquiring as many as 11 consecutive rings within a five-minute period. In total, the study group successfully acquired over 85% of presented targets. These results affirm the effective, three-dimensional control of our motor imagery based BCI system, and suggest its potential applications in biological navigation, neuroprosthetics, and other applications.

Prognostic factors for the incidence and recovery of delayed facial nerve palsy after vestibular schwannoma resection.

OBJECT: Preservation of facial nerve function in vestibular schwannoma (VS) resections remains a significant operative challenge. Delayed facial palsy (DFP) is one specific challenge yet to be fully elucidated. The aim of this study was to evaluate DFP among VS resection cases to identify significant prognostic factors associated with its incidence and clinical recovery. METHODS: This investigation involves a retrospective review of 104 cases of VS resection that occurred between December 2005 and May 2007. Patients who developed DFP were compared with patients exhibiting no facial palsy postoperatively with regard to surgical approach, severity and day of palsy onset, tumor size, intraoperative facial nerve monitoring, and postoperative recovery and treatment. Patients who demonstrated immediate facial palsy (IFP) following VS resection were also analyzed. Furthermore, specific analyses were performed in 2 distinct DFP patient groups: those who developed DFP after postoperative Day 3 ("late onset DFP"), and those whose palsy worsened after initial DFP identification ("deteriorators"). RESULTS: Of the 104 patients who underwent VS resection, 25.0% developed DFP and 8.6% demonstrated IFP postoperatively. The DFP group did not differ significantly in any measure when compared with patients with no postoperative facial palsy. However, patients with DFP presented with significantly smaller tumor sizes than patients with IFP. This IFP group averaged significantly smaller intraoperative facial nerve responses than patients without facial palsy, and larger tumor sizes than both the DFP and no facial palsy groups. Within the DFP group, patients with late onset DFP showed diminished intraoperative facial nerve responses when compared with the total DFP patient population. In total, 25 (96.2%) of 26 patients with DFP and 7 (77.8%) of 9 patients with IFP recovered to normal or near-normal facial function (House-Brackmann Grade I or II) at longest clinical follow-up. CONCLUSIONS: Although patients with DFP did not exhibit any distinguishable characteristics when compared with patients without postoperative facial palsy, our analysis identified significant differences in patients with palsy presenting immediately postoperatively. Further study of patients with DFP should be undertaken to predict its incidence following VS resection.

Hearing preservation in the resection of vestibular schwannomas: patterns of hearing preservation and patient-assessed hearing function.

OBJECT: No extant literature documents the analysis of patient perceptions of hearing as a corollary to objective audiometric measures in patients with vestibular schwannoma (VS), or acoustic neuroma. Therefore, using objective audiometric data and patient perceptions of hearing function as outlined on a questionnaire, the authors evaluated the hearing of patients who underwent VS resection. METHODS: This investigation involved a retrospective review of 176 patients who had undergone VS resections in which hearing preservation was a goal. Both pre- and postoperative audiometry, expressed as a speech discrimination score (SDS) and pure tone threshold average (PTA), were performed, and the results were analyzed. Intraoperative auditory brainstem responses were also recorded. Eighty-seven of the patients (49.4%) completed a postoperative questionnaire designed to assess hearing function in a variety of social and auditory situations. Multiple linear regression analyses were completed to compare available audiometric results with questionnaire responses for each patient. RESULTS: One hundred forty-two patients (80.7%) had PTA and SDS audiometric data pertaining to the surgically treated ear; 94 of these patients (66.2%) had measurable postoperative hearing, as defined by a PTA < 120 dB or SD > 0%. Eighty-seven patients (49.4%) completed the retrospective questionnaire, and 74 of them had complete audiometric data and thus were included in a comparative analysis. Questionnaire data showed major postoperative subjective hearing decrements, even among patients with the same pre- and postoperative objective audiometric hearing status. Moreover, the subscore reflecting hearing while exposed to background noise, or the "cocktail party effect," characterized the most significant patient-perceived hearing deficit following VS resection. CONCLUSIONS: The authors' analysis of a patient-perceived hearing questionnaire showed that hearing during exposure to background noise, or the cocktail party effect, represents a significant postoperative hearing deficit and that patient perception of this deficit has a strong relation with audiometric data. Furthermore, questionnaire responses revealed a significant disparity between subjective hearing function and standard audiometrics such that even with similar levels of audiometric data, subjective measures of hearing, especially the cocktail party effect, decreased postoperatively. The authors posit that the incorporation of patient-perceived hearing function evaluation along with standard audiometry is an illustrative means of identifying subjective hearing deficits after VS resection and may ultimately aid in specific and subsequent treatment for these patients.

What's new in the diagnosis and treatment of peripheral nerve entrapment neuropathies.

Entrapment neuropathies can be common conditions with the potential to cause significant disability. Correct diagnosis is essential for proper management. This article is a review of recent developments related to diagnosis and treatment of various common and uncommon nerve entrapment disorders. When combined with classical peripheral nerve examination techniques, innovations in imaging modalities have led to more reliable diagnoses. Moreover, innovations in conservative and surgical techniques have been controversial as to their effects on patient outcome, but randomized controlled trials have provided important information regarding common operative techniques. Treatment strategies for painful peripheral neuropathies are also reviewed.