Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice.

Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits, individuals with WBS have spared or enhanced musical and auditory abilities, potentially offering an insight into the genetic basis of auditory perception. Here, we report that the mouse models of WBS have innately enhanced frequency-discrimination acuity and improved frequency coding in the auditory cortex (ACx). Chemogenetic rescue showed frequency-discrimination hyperacuity is caused by hyperexcitable interneurons in the ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in the ACx of individuals with WBS and in the cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Vipr1 deletion or overexpression in ACx interneurons mimicked or reversed, respectively, the cellular and behavioral phenotypes of WBS mice. Thus, the Gtf2ird1-Vipr1 mechanism in ACx interneurons may underlie the superior auditory acuity in WBS.

Cortical control of striatal fast-spiking interneuron synchrony.

Inhibitory fast-spiking interneurons in the dorsal striatum regulate actions and action strategies, including habits. Fast-spiking interneurons are widely believed to synchronize their firing due to the electrical synapses formed between these neurons. However, neuronal modelling data suggest convergent cortical input may also drive synchrony in fast-spiking interneuron networks. To better understand how fast-spiking interneuron synchrony arises, we performed dual whole-cell patch clamp electrophysiology experiments to inform a simple Bayesian network modelling cortico-fast-spiking interneuron circuitry. Dual whole-cell patch clamp electrophysiology revealed that while responsivity to corticostriatal input activation was high in fast-spiking interneurons, few of these neurons exhibited electrical coupling in adult mice. In simulations of a cortico-fast-spiking interneuron network informed by these data, the degree of glutamatergic cortical convergence onto fast-spiking interneurons significantly increased fast-spiking interneuron synchronization while manipulations of electrical coupling between these neurons exerted relatively little impact. These results suggest that the primary source of functional coordination of fast-spiking interneuron activity in adulthood arises from convergent corticostriatal input activation. KEY POINTS: Electrical synapses between striatal fast-spiking interneurons in adult mice occur in ∼8% of assayed pairs. Coincident, convergent cortical input onto fast-spiking interneurons significantly contributes to fast-spiking interneuron synchrony. Electrical synapses between fast-spiking interneurons provide only minor enhancement of fast-spiking interneuron synchrony. These results suggest a mechanism by which adult mouse fast-spiking interneurons of the striatum synchronize in the face of declining expression of the electrical synapse-forming connexin-36 protein.

Physiotherapists Both Reproduce and Resist Biomedical Dominance when Working With People With Low Back Pain: A Qualitative Study Towards New Praxis.

Despite recommendations to incorporate physical and psychosocial factors when providing care for people with back pain, research suggests that physiotherapists continue to focus on biological aspects. This study investigated how interpersonal and institutional norms influence this continued enactment of the biological aspects of management. We used theoretically-driven analysis, drawing from Foucauldian notions of power, to analyse 28 ethnographic observations of consultations and seven group discussions with physiotherapists. Analysis suggested that physiotherapy training established expectations of what a physiotherapist 'should' focus on, and institutional circumstances strongly drew the attention of physiotherapists towards biological aspects. Resistance to these forces was possible when, for example, physiotherapists reflected upon their practice, used silences and pauses during consultations, and actively collaborated with patients. These circumstances facilitated use of non-biomedical management approaches. Findings may assist physiotherapists to rework the enduring normative focus on biomedical aspects of care when providing care for patients with back pain.

Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival.

Pancreatic tumors are highly desmoplastic and poorly-vascularized, and therefore must develop adaptive mechanisms to sustain their survival under hypoxic condition. Extracellular vesicles (EV) play vital roles in pancreatic tumor pathobiology by facilitating intercellular communication. Here we studied the effect of hypoxia on the release of EVs and examined their role in adaptive survival of pancreatic cancer (PC) cells. Hypoxia promoted the release of EV in PC cell lines, MiaPaCa and AsPC1, wherein former exhibited a far greater induction. Moreover, a time-dependent, measurable and significant increase was recorded for small EV (SEV) in both the cell lines with only minimal induction observed for medium (MEV) and large EVs (LEV). Similarly, noticeable changes in size distribution of SEV were also recorded with a shift toward smaller average size under extreme hypoxia. Thrombospondin (apoptotic bodies marker) was exclusively detected on LEVs, while Arf6 (microvesicles marker) was mostly present on MEV with some expression in LEV as well. However, CD9 and CD63 (exosome markers) were expressed in both SEV and MEVs with a decreased expression recorded under hypoxia. Among all subfractions, SEV was the most bioactive in promoting the survival of hypoxic PC cells and hypoxia-inducible factor-1α stabilization was involved in heightened EV release under hypoxia and for their potency to promote hypoxic cell survival. Altogether, our findings provide a novel mechanism for the adaptive hypoxic survival of PC cells and should serve as the basis for future investigations on broader functional implications of EV.

Complex Control of Striatal Neurotransmission by Nicotinic Acetylcholine Receptors via Excitatory Inputs onto Medium Spiny Neurons.

The prevalence of nicotine dependence is higher than that for any other substance abuse disorder; still, the underlying mechanisms are not fully established. To this end, we studied acute effects by nicotine on neurotransmission in the dorsolateral striatum, a key brain region with respect to the formation of habits. Electrophysiological recordings in acutely isolated brain slices from rodent showed that nicotine (10 nm to 10 µm) produced an LTD of evoked field potentials. Current-clamp recordings revealed no significant effect by nicotine on membrane voltage or action potential frequency, indicating that the effect by nicotine is primarily synaptic. Nicotine did not modulate sIPSCs, or the connectivity between fast-spiking interneurons and medium spiny neurons, as assessed by whole-cell recordings combined with optogenetics. However, the frequency of sEPSCs was significantly depressed by nicotine. The effect by nicotine was mimicked by agonists targeting α7- or α4-containing nAChRs and blocked in slices pretreated with a mixture of antagonists targeting these receptor subtypes. Nicotine-induced LTD was furthermore inhibited by dopamine D2 receptor antagonist and occluded by D2 receptor agonist. In addition, modulation of cholinergic neurotransmission suppressed the responding to nicotine, which might reflect upon the postulated role for nAChRs as a presynaptic filter to differentially govern dopamine release depending on neuronal activity. Nicotine-induced suppression of excitatory inputs onto medium spiny neurons may promote nicotine-induced locomotor stimulation and putatively initiate neuroadaptations that could contribute to the transition toward compulsive drug taking.SIGNIFICANCE STATEMENT To decrease smoking, prevalence factors that may contribute to the development of nicotine addiction need to be identified. The data presented here show that nicotine suppresses striatal neurotransmission by selectively reducing the frequency of excitatory inputs to medium spiny neurons (MSNs) while rendering excitability, inhibitory neurotransmission, and fast-spiking interneuron-MSN connectivity unaltered. In addition, we show that the effect displayed by nicotine outlasts the presence of the drug, which could be fundamental for the addictive properties of nicotine. Considering the inhibitory tone displayed by MSNs on dopaminergic cell bodies and local terminals, nicotine-induced long-lasting depression of striatal output could play a role in behavioral transformations associated with nicotine use, and putatively elicit neuroadaptations underlying compulsive drug-seeking habits.

Understanding functional and social risk characteristics of frail older adults: a cross-sectional survey study.

BACKGROUND: Frailty is a condition of increasing importance, given the aging adult population. With an anticipated shortage of geriatricians, primary care physicians will increasingly need to manage care for frail adults with complex functional risks and social-economic circumstances. METHODS: We used cross-sectional data from 4551 adults ages 65-90 who responded to the 2014/2015 cycle of the Kaiser Permanente Northern California Member Health Survey (MHS), a self-administered survey that covers multiple health and social characteristics, to create a deficits accumulation model frailty index, classify respondents as frail or non-frail, and then compare prevalence of functional health issues including Activities of Daily Living (ADL)/Instrumental Activities of Daily Living (IADL) and social determinants of health (SDOHs) by frailty status. RESULTS: The overall prevalence of frailty was 14.3%, higher for women than men, increased with age, and more common among those with low levels of education and income. Frail older adults were more likely than non-frail to have ≥ 3 chronic diseases (55.9% vs. 10.1%), obesity (32.7% vs. 22.8%), insomnia (36.4% vs. 8.8%), oral health problems (25.1% vs. 4.7%), balance or walking problems (54.2% vs. 4.9%), ≥ 1 fall (56.1% vs. 19.7%), to use ≥ 1 medication known to increase fall risk (56.7% vs. 26.0%), and to need help with ≥2 ADLs (15.8% vs. 0.8%) and ≥ 2 IADLs (38.4% vs. 0.8%). They were more likely to feel financial strain (26.9% vs. 12.6%) and to use less medication than prescribed (7.4% vs. 3.6%), less medical care than needed (8.3% vs 3.7%), and eat less produce (9.5% vs. 3.2%) due to cost. Nearly 20% of frail adults were unpaid caregivers for an adult with frailty, serious illness or disability. CONCLUSIONS: This study examined the prevalence of frailty and identified modifiable and non-modifiable risk factors of health. The frail older adult population is heterogeneous and requires a patient-centered assessment of their circumstances by healthcare providers and caregivers to improve their quality of life, avoid adverse health events, and slow physical and mental decline. The characteristics identified in this study can be proactively used for the assessment of patient health, quality of life, and frailty prevention.

Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK.

BACKGROUND: Chemoresistance is a significant clinical problem in pancreatic cancer (PC) and underlying molecular mechanisms still remain to be completely understood. Here we report a novel exosome-mediated mechanism of drug-induced acquired chemoresistance in PC cells. METHODS: Differential ultracentrifugation was performed to isolate extracellular vesicles (EVs) based on their size from vehicle- or gemcitabine-treated PC cells. Extracellular vesicles size and subtypes were determined by dynamic light scattering and marker profiling, respectively. Gene expression was examined by qRT-PCR and/or immunoblot analyses, and direct targeting of DCK by miR-155 was confirmed by dual-luciferase 3'-UTR reporter assay. Flow cytometry was performed to examine the apoptosis indices and reactive oxygen species (ROS) levels in PC cells using specific dyes. Cell viability was determined using the WST-1 assay. RESULTS: Conditioned media (CM) from gemcitabine-treated PC cells (Gem-CM) provided significant chemoprotection to subsequent gemcitabine toxicity and most of the chemoresistance conferred by Gem-CM resulted from its EVs fraction. Sub-fractionation grouped EVs into distinct subtypes based on size distribution and marker profiles, and exosome (Gem-Exo) was the only sub-fraction that imparted chemoresistance. Gene expression analyses demonstrated upregulation of SOD2 and CAT (ROS-detoxifying genes), and downregulation of DCK (gemcitabine-metabolising gene) in Gem-Exo-treated cells. SOD/CAT upregulation resulted, at least in part, from exosome-mediated transfer of their transcripts and they suppressed basal and gemcitabine-induced ROS production, and partly promoted chemoresistance. DCK downregulation occurred through exosome-delivered miR-155 and either the functional suppression of miR-155 or restoration of DCK led to marked abrogation of Gem-Exo-mediated chemoresistance. CONCLUSIONS: Together, these findings establish a novel role of exosomes in mediating the acquired chemoresistance of PC.

Experience of clinical supervisors of international medical graduates in an Australian district hospital.

Objective Herein we record the experience of clinical supervisors of international medical graduates (IMGs) working as junior staff in a district hospital by examining supervisor perspectives on IMG performance, the factors affecting their performance and the requirements of supervision under these circumstances. Methods The present study had an open-ended exploratory qualitative design. Thirteen 13 open-ended, in-depth interviews were undertaken with supervisors of IMGs employed in a public district hospital in Queensland, Australia. Results The supervisors reported that, although performance was an individual and variable characteristic, IMGs tended to perform less well than Australian graduates and required more intensive supervision. Factors that affected performance were motivation and experience, and specifically lack of familiarity with the Australian healthcare system, lack of recent of practice, education, language, communication and cultural factors. English language proficiency was regarded as crucial to performance. Conclusions The additional work required to supervise IMGs in order to enable them to perform at a satisfactory level and successfully integrate into the Australian healthcare system needs to be recognised and resourced. Assistance with attaining proficiency in English and with communication skills over and above the standard required to pass the International English Language Testing System examination should be seriously considered as a means of improving performance. What is known about the topic? To date, there is little research available about the experience of supervisors of IMGs in Australia. What does this paper add? The findings of the present study make an important contribution to the literature by examining the critical role clinical supervisors of IMGs have in helping IMGs adapt to the Australian healthcare system and ensuring that they are able to provide quality health care. It identifies current challenges and highlights areas in need of attention to ensure a strong healthcare system for Australia. What are the implications for practitioners? Supervisors of IMGs need recognition of the extra time and expertise required in their role if they are to be effectively supported in their endeavours to integrate IMGs into the Australian health workforce. More attention needs to be given to the development of English language proficiency of IMGs, including colloquial usage, and communication in medical practice.

Role of the prefrontal cortex in altered hippocampal-accumbens synaptic plasticity in a developmental animal model of schizophrenia.

Schizophrenia is characterized by alterations in cortico-limbic processes believed to involve modifications in activity within the prefrontal cortex (PFC) and the hippocampus. The nucleus accumbens (NAc) integrates information from these 2 brain regions and is involved in cognitive and psychomotor functions that are disrupted in schizophrenia, indicating an important role for this structure in the pathophysiology of this disorder. In this study, we used in vivo electrophysiological recordings from the NAc and the PFC of adult rats and the MAM developmental disruption rodent model of schizophrenia to explore the influence of the medial PFC on the hippocampal-accumbens pathway. We found that, in MAM-treated rats, tetanization of hippocampal inputs to the NAc produce opposite synaptic plasticity compared with controls, which is a consequence of alterations in the hippocampal-mPFC pathway. Moreover, we show that administration of the D2-receptor-blocking antipsychotic drug sulpiride either systemically or directly into the mPFC reverses the alterations in the MAM rat. Therefore, specific disruptions in cortical and hippocampal inputs in the MAM-treated rat abnormally alter plasticity in subcortical structures. Moreover, our results suggest that, in the presence of antipsychotic drugs, the disrupted plasticities are normalized, supporting a role for this mechanism in antipsychotic drug action in schizophrenia.

The infralimbic cortex bidirectionally modulates mesolimbic dopamine neuron activity via distinct neural pathways.

The ventral tegmental area (VTA) has been implicated in a number of psychiatric disorders, including schizophrenia, depression, and bipolar disorder. One major regulator of the mesolimbic dopaminergic system is the medial prefrontal cortex (mPFC), which makes direct and indirect connections to the hippocampus and amygdala, as well as directly to the VTA. The mPFC is comprised of two subregions: the infralimbic and prelimbic cortices (ilPFC and plPFC). However, the specific roles of these subregions in regulating VTA dopamine activity have remained unclear. In this study, we aim to clarify this role and to examine the divergent neuranatomical circuits by which the mPFC regulates VTA activity. Using in vivo extracellular recordings in rats, we tested the effects of pharmacological activation (with NMDA) and inactivation (with TTX) of the ilPFC and plPFC on dopamine neuron activity, and tested the roles of the ventral subiculum (vSub) and basolateral amygdala in this process. We found that the ilPFC exerts a bidirectional control of VTA dopamine neurons, which are differentially modulated through the vSub and the basolateral amygdala. Specifically, activation or inactivation of the ilPFC attenuated or activated dopamine neuron population activity, respectively. Furthermore, dopamine activation depended on the ventral hippocampus and inactivation on the amygdala. In contrast, only inactivation of the plPFC altered dopamine neuron activity. These data indicate that the mPFC has the ability to uniquely fine-tune dopaminergic activity in the VTA. Furthermore, the data presented here suggest that the ilPFC may have a role in the pathophysiology of psychiatric disorders.

Synaptic plasticity in human thalamocortical assembloids.

Synaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell-derived thalamic and cortical organoids. Single-nucleus RNA-sequencing revealed that most cells in mature thalamic organoids were glutamatergic neurons. When fused to form thalamocortical assembloids, thalamic and cortical organoids formed reciprocal long-range axonal projections and reciprocal synapses detectable by light and electron microscopy, respectively. Using whole-cell patch-clamp electrophysiology and two-photon imaging, we characterized glutamatergic synaptic transmission. Thalamocortical and corticothalamic synapses displayed short-term plasticity analogous to that in animal models. LTP and LTD were reliably induced at both synapses; however, their mechanisms differed from those previously described in rodents. Thus, thalamocortical assembloids provide a model system for exploring synaptic plasticity in human circuits.

Synaptic plasticity in human thalamocortical assembloids.

Synaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell-derived thalamic and cortical organoids. Single-nucleus RNA sequencing revealed that >80% of cells in thalamic organoids were glutamatergic neurons. When fused to form thalamocortical assembloids, thalamic and cortical organoids formed reciprocal long-range axonal projections and reciprocal synapses detectable by light and electron microscopy, respectively. Using whole-cell patch-clamp electrophysiology and two-photon imaging, we characterized glutamatergic synaptic transmission. Thalamocortical and corticothalamic synapses displayed short-term plasticity analogous to that in animal models. LTP and LTD were reliably induced at both synapses; however, their mechanisms differed from those previously described in rodents. Thus, thalamocortical assembloids provide a model system for exploring synaptic plasticity in human circuits.

Disruption of prefrontal cortical-hippocampal balance in a developmental model of schizophrenia: reversal by sulpiride.

The nucleus accumbens (NAc) receives converging inputs from the medial prefrontal cortex (mPFC) and the hippocampus which have competitive interactions in the NAc to influence motivational drive. We have previously shown altered synaptic plasticity in the hippocampal-NAc pathway in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in rodents that is dependent on cortical inputs. Thus, because mPFC-hippocampal balance is known to be partially altered in this model, we investigated potential pathological changes in the hippocampal influence over cortex-driven NAc spike activity. Here we show that the reciprocal interaction between the hippocampus and mPFC is absent in MAM animals but is able to be reinstated with administration of the antipsychotic drug, sulpiride. The lack of interaction between these structures in this model could explain the attentional deficits in schizophrenia patients and shed light onto their inability to focus on a single task.

Selective chemogenetic inactivation of corticoaccumbal projections disrupts trait choice impulsivity.

Impulsive choice has enduring trait-like characteristics and is defined by preference for small immediate rewards over larger delayed ones. Importantly, it is a determining factor in the development and persistence of substance use disorder (SUD). Emerging evidence from human and animal studies suggests frontal cortical regions exert influence over striatal reward processing areas during decision-making in impulsive choice or delay discounting (DD) tasks. The goal of this study was to examine how these circuits are involved in decision-making in animals with defined trait impulsivity. To this end, we trained adolescent male rats to stable behavior on a DD procedure and then re-trained them in adulthood to assess trait-like, conserved impulsive choice across development. We then used chemogenetic tools to selectively and reversibly target corticostriatal projections during performance of the DD task. The prelimbic region of the medial prefrontal cortex (mPFC) was injected with a viral vector expressing inhibitory designer receptors exclusively activated by designer drugs (Gi-DREADD), and then mPFC projections to the nucleus accumbens core (NAc) were selectively suppressed by intra-NAc administration of the Gi-DREADD actuator clozapine-n-oxide (CNO). Inactivation of the mPFC-NAc projection elicited a robust increase in impulsive choice in rats with lower vs. higher baseline impulsivity. This demonstrates a fundamental role for mPFC afferents to the NAc during choice impulsivity and suggests that maladaptive hypofrontality may underlie decreased executive control in animals with higher levels of choice impulsivity. Results such as these may have important implications for the pathophysiology and treatment of impulse control, SUDs, and related psychiatric disorders.

Patterns in Tacrolimus Variability and Association with De Novo Donor-Specific Antibody Formation in Pediatric Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: High tacrolimus intrapatient variability has been associated with inferior graft outcomes in patients with kidney transplants. We studied baseline patterns of tacrolimus intrapatient variability in pediatric patients with kidney transplants and examined these patterns in relation to C1q-binding de novo donor-specific antibodies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All tacrolimus levels in participants who underwent kidney-only transplantation at a single pediatric center from 2004 to 2018 (with at least 12-month follow-up, followed until 2019) were analyzed to determine baseline variability. Intrapatient variability was defined using the coefficient of variation (SD/mean ×100%) of all samples in a 6-month moving window. Routine de novo donor-specific antibody measurements were available for a subgroup of patients transplanted in 2010-2018. Cox proportional hazards models using tacrolimus intrapatient variability as a time-varying variable were used to examine the association between intrapatient variability and graft outcomes. The primary outcome of interest was C1q-binding de novo donor-specific antibody formation. RESULTS: Tacrolimus intrapatient variability developed a steady-state baseline of 30% at 10 months post-transplant in 426 patients with a combined 31,125 tacrolimus levels. Included in the outcomes study were 220 patients, of whom 51 developed C1q-binding de novo donor-specific antibodies. De novo donor-specific antibody formers had higher intrapatient variability, with a median of 38% (interquartile range, 28%-48%) compared with 28% (interquartile range, 20%-38%) for nondonor-specific antibody formers (P<0.001). Patients with high tacrolimus intrapatient variability (coefficient of variation >30%) had higher risk of de novo donor-specific antibody formation (hazard ratio, 5.35; 95% confidence interval, 2.45 to 11.68). Patients in the top quartile of tacrolimus intrapatient variability (coefficient of variation >41%) had the strongest association with C1q-binding de novo donor-specific antibody formation (hazard ratio, 11.81; 95% confidence interval, 4.76 to 29.27). CONCLUSIONS: High tacrolimus intrapatient variability was strongly associated with de novo donor-specific antibody formation.

Alzheimer's disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment.

Recent proteome and transcriptome profiling of Alzheimer's disease (AD) brains reveals RNA splicing dysfunction and U1 small nuclear ribonucleoprotein (snRNP) pathology containing U1-70K and its N-terminal 40-KDa fragment (N40K). Here we present a causative role of U1 snRNP dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70K. N40K-Tg recapitulates N40K insolubility, erroneous splicing events, neuronal degeneration and cognitive impairment. Specifically, N40K-Tg shows the reduction of GABAergic synapse components (e.g., the GABA receptor subunit of GABRA2), and concomitant postsynaptic hyperexcitability that is rescued by a GABA receptor agonist. Crossing of N40K-Tg and the 5xFAD amyloidosis model indicates that the RNA splicing defect synergizes with the amyloid cascade to remodel the brain transcriptome and proteome, deregulate synaptic proteins, and accelerate cognitive decline. Thus, our results support the contribution of U1 snRNP-mediated splicing dysfunction to AD pathogenesis.

A Case for Thalamic Mechanisms of Schizophrenia: Perspective From Modeling 22q11.2 Deletion Syndrome.

Schizophrenia is a severe, chronic psychiatric disorder that devastates the lives of millions of people worldwide. The disease is characterized by a constellation of symptoms, ranging from cognitive deficits, to social withdrawal, to hallucinations. Despite decades of research, our understanding of the neurobiology of the disease, specifically the neural circuits underlying schizophrenia symptoms, is still in the early stages. Consequently, the development of therapies continues to be stagnant, and overall prognosis is poor. The main obstacle to improving the treatment of schizophrenia is its multicausal, polygenic etiology, which is difficult to model. Clinical observations and the emergence of preclinical models of rare but well-defined genomic lesions that confer substantial risk of schizophrenia (e.g., 22q11.2 microdeletion) have highlighted the role of the thalamus in the disease. Here we review the literature on the molecular, cellular, and circuitry findings in schizophrenia and discuss the leading theories in the field, which point to abnormalities within the thalamus as potential pathogenic mechanisms of schizophrenia. We posit that synaptic dysfunction and oscillatory abnormalities in neural circuits involving projections from and within the thalamus, with a focus on the thalamocortical circuits, may underlie the psychotic (and possibly other) symptoms of schizophrenia.

"I was never like that": Australian findings on the psychological and psychiatric sequelae of corticosteroids in haematology treatments.

GOALS OF WORK: Corticosteroid treatments have been well documented to cause severe emotional and even psychiatric disturbances. Despite that corticosteroid use is at the core of most treatment protocols for haematological malignancies, there is a dearth of published research (and controversy in the existing research) on the emotional and psychiatric sequelae of corticosteroid use for haematology patients and its connection with pre-existing mental history. This paper aims to address this hiatus and confusion by examining the emotional and psychiatric side effects of corticosteroids on haematology patients in Australia. MATERIALS AND METHODS: The findings are from a pilot study that explored the prior mental health history and effects of corticosteroid use of ten haematology patients in Australia. Data was collected through an iterative, phenomenological, qualitative research methodology using open-ended interviews conducted at the time and location of the participant's choice. The interviews were audio-recorded and transcribed verbatim. The language texts were then entered into the QSR NUD*IST computer program and analysed thematically. MAIN RESULTS: The significant finding from the study was that corticosteroids used in haematology treatments have the potential to affect anyone and are not related to an individual's prior mental health history. No participant presented evidence of psychiatric history or counseling and many reported emotional stability during previous times of difficulty. All participants reported emotional distress directly related to corticosteroid use. Participants reported difficulties during the period of withdrawal from corticosteroids and relief during periods free from the administration of corticosteroids. CONCLUSIONS: The findings provide evidence that emotional disturbances associated with corticosteroid use in haematology are a direct result of the drugs used and not a symptom of the individual's prior emotional health. Recommendations are given which have important implications for the management, support and education of patients and their families in relation to the potential emotional side effects from steroid administration and withdrawal.

Rejuvenation of plasticity in the brain: opening the critical period.

Cortical circuits are particularly sensitive to incoming sensory information during well-defined intervals of postnatal development called 'critical periods'. The critical period for cortical plasticity closes in adults, thus restricting the brain's ability to indiscriminately store new sensory information. For example, children acquire language in an exposure-based manner, whereas learning language in adulthood requires more effort and attention. It has been suggested that pairing sounds with the activation of neuromodulatory circuits involved in attention reopens this critical period. Here, we review two critical period hypotheses related to neuromodulation: cortical disinhibition and thalamic adenosine. We posit that these mechanisms co-regulate the critical period for auditory cortical plasticity. We also discuss ways to reopen this period and rejuvenate cortical plasticity in adults.