A developmentally defined population of neurons in the lateral septum controls responses to aversive stimuli.

When interacting with their environment, animals must balance exploratory and defensive behavior to evaluate and respond to potential threats. The lateral septum (LS) is a structure in the ventral forebrain that calibrates the magnitude of behavioral responses to stress-related external stimuli, including the regulation of threat avoidance. The complex connectivity between the LS and other parts of the brain, together with its largely unexplored neuronal diversity, makes it difficult to understand how defined LS circuits control specific behaviors. Here, we describe a mouse model in which a population of neurons with a common developmental origin (Nkx2.1-lineage neurons) are absent from the LS. Using a combination of circuit tracing and behavioral analyses, we found that these neurons receive inputs from the perifornical area of the anterior hypothalamus (PeFAH) and are specifically activated in stressful contexts. Mice lacking Nkx2.1-lineage LS neurons display increased exploratory behavior even under stressful conditions. Our study extends the current knowledge about how defined neuronal populations within the LS can evaluate contextual information to select appropriate behavioral responses. This is a necessary step towards understanding the crucial role that the LS plays in neuropsychiatric conditions where defensive behavior is dysregulated, such as anxiety and aggression disorders.

Revealing the structure of pharmacobehavioral space through motion sequencing.

Understanding how genes, drugs and neural circuits influence behavior requires the ability to effectively organize information about similarities and differences within complex behavioral datasets. Motion Sequencing (MoSeq) is an ethologically inspired behavioral analysis method that identifies modular components of three-dimensional mouse body language called 'syllables'. Here, we show that MoSeq effectively parses behavioral differences and captures similarities elicited by a panel of neuroactive and psychoactive drugs administered to a cohort of nearly 700 mice. MoSeq identifies syllables that are characteristic of individual drugs, a finding we leverage to reveal specific on- and off-target effects of both established and candidate therapeutics in a mouse model of autism spectrum disorder. These results demonstrate that MoSeq can meaningfully organize large-scale behavioral data, illustrate the power of a fundamentally modular description of behavior and suggest that behavioral syllables represent a new class of druggable target.

The Striatum Organizes 3D Behavior via Moment-to-Moment Action Selection.

Many naturalistic behaviors are built from modular components that are expressed sequentially. Although striatal circuits have been implicated in action selection and implementation, the neural mechanisms that compose behavior in unrestrained animals are not well understood. Here, we record bulk and cellular neural activity in the direct and indirect pathways of dorsolateral striatum (DLS) as mice spontaneously express action sequences. These experiments reveal that DLS neurons systematically encode information about the identity and ordering of sub-second 3D behavioral motifs; this encoding is facilitated by fast-timescale decorrelations between the direct and indirect pathways. Furthermore, lesioning the DLS prevents appropriate sequence assembly during exploratory or odor-evoked behaviors. By characterizing naturalistic behavior at neural timescales, these experiments identify a code for elemental 3D pose dynamics built from complementary pathway dynamics, support a role for DLS in constructing meaningful behavioral sequences, and suggest models for how actions are sculpted over time.

Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber.

Optogenetics promises precise spatiotemporal control of neural processes using light. However, the spatial extent of illumination within the brain is difficult to control and cannot be adjusted using standard fiber optics. We demonstrate that optical fibers with tapered tips can be used to illuminate either spatially restricted or large brain volumes. Remotely adjusting the light input angle to the fiber varies the light-emitting portion of the taper over several millimeters without movement of the implant. We use this mode to activate dorsal versus ventral striatum of individual mice and reveal different effects of each manipulation on motor behavior. Conversely, injecting light over the full numerical aperture of the fiber results in light emission from the entire taper surface, achieving broader and more efficient optogenetic activation of neurons, compared to standard flat-faced fiber stimulation. Thus, tapered fibers permit focal or broad illumination that can be precisely and dynamically matched to experimental needs.

Mapping Sub-Second Structure in Mouse Behavior.

Complex animal behaviors are likely built from simpler modules, but their systematic identification in mammals remains a significant challenge. Here we use depth imaging to show that 3D mouse pose dynamics are structured at the sub-second timescale. Computational modeling of these fast dynamics effectively describes mouse behavior as a series of reused and stereotyped modules with defined transition probabilities. We demonstrate this combined 3D imaging and machine learning method can be used to unmask potential strategies employed by the brain to adapt to the environment, to capture both predicted and previously hidden phenotypes caused by genetic or neural manipulations, and to systematically expose the global structure of behavior within an experiment. This work reveals that mouse body language is built from identifiable components and is organized in a predictable fashion; deciphering this language establishes an objective framework for characterizing the influence of environmental cues, genes and neural activity on behavior.

An adaptive filtered back-projection for photoacoustic image reconstruction.

PURPOSE: The purpose of this study is to develop an improved filtered-back-projection (FBP) algorithm for photoacoustic tomography (PAT), which allows image reconstruction with higher quality compared to images reconstructed through traditional algorithms. METHODS: A rigorous expression of a weighting function has been derived directly from a photoacoustic wave equation and used as a ramp filter in Fourier domain. The authors' new algorithm utilizes this weighting function to precisely calculate each photoacoustic signal's contribution and then reconstructs the image based on the retarded potential generated from the photoacoustic sources. In addition, an adaptive criterion has been derived for selecting the cutoff frequency of a low pass filter. Two computational phantoms were created to test the algorithm. The first phantom contained five spheres with each sphere having different absorbances. The phantom was used to test the capability for correctly representing both the geometry and the relative absorbed energy in a planar measurement system. The authors also used another phantom containing absorbers of different sizes with overlapping geometry to evaluate the performance of the new method for complicated geometry. In addition, random noise background was added to the simulated data, which were obtained by using an arc-shaped array of 50 evenly distributed transducers that spanned 160° over a circle with a radius of 65 mm. A normalized factor between the neighbored transducers was applied for correcting measurement signals in PAT simulations. The authors assumed that the scanned object was mounted on a holder that rotated over the full 360° and the scans were set to a sampling rate of 20.48 MHz. RESULTS: The authors have obtained reconstructed images of the computerized phantoms by utilizing the new FBP algorithm. From the reconstructed image of the first phantom, one can see that this new approach allows not only obtaining a sharp image but also showing the correct signal strength of the absorbers. The reconstructed image of the second phantom further demonstrates the capability to form clear images of the spheres with sharp borders in the overlapping geometry. The smallest sphere is clearly visible and distinguishable, even though it is surrounded by two big spheres. In addition, image reconstructions were conducted with randomized noise added to the observed signals to mimic realistic experimental conditions. CONCLUSIONS: The authors have developed a new FBP algorithm that is capable for reconstructing high quality images with correct relative intensities and sharp borders for PAT. The results demonstrate that the weighting function serves as a precise ramp filter for processing the observed signals in the Fourier domain. In addition, this algorithm allows an adaptive determination of the cutoff frequency for the applied low pass filter.

Label-free detection of cardiac troponin I with a photonic crystal biosensor.

A biosensor has been developed with a photonic crystal structure used in a total-internal-reflection (PC-TIR) configuration for label-free detection of a cardiac biomarker: Troponin I (cTnI). In contrast to a conventional optical microcavity that has a closed structure with its cavity layer sandwiched between two high-reflection surfaces, the PC-TIR configuration creates a unique open microcavity, which allows its cavity layer (sensing layer) to be easily functionalized and directly exposed to analyte molecules for bioassays. In this study, a PC-TIR sensor has been used for the label-free measurements of cardiac biomarkers by monitoring the changes in the resonant condition of the cavity due to biomolecular binding processes. Antibodies against cTnI are immobilized on the sensor surface for specific detection of cTnI with a wide range of concentrations. Detection limit of cTnI with a concentration as low as 0.1ngmL(-1) has been achieved.

Sensitivity enhancement of an open-cavity-based optoacoustic sensor.

We present a new method for sensitive ultrasound detection using an open-cavity optoacoustic sensor. Our results have demonstrated significant enhancement of detection sensitivity when the open-cavity sensor is used in media with large isothermal compressibility. A near-linear relationship between detected optoacoustic signal strength and isothermal compressibility has been found.

Detection of Myoglobin with an Open-Cavity-Based Label-Free Photonic Crystal Biosensor.

The label-free detection of one of the cardiac biomarkers, myoglobin, using a photonic-crystal-based biosensor in a total-internal-reflection configuration (PC-TIR) is presented in this paper. The PC-TIR sensor possesses a unique open optical microcavity that allows for several key advantages in biomolecular assays. In contrast to a conventional closed microcavity, the open configuration allows easy functionalization of the sensing surface for rapid biomolecular binding assays. Moreover, the properties of PC structures make it easy to be designed and engineered for operating at any optical wavelength. Through fine design of the photonic crystal structure, biochemical modification of the sensor surface, and integration with a microfluidic system, we have demonstrated that the detection sensitivity of the sensor for myoglobin has reached the clinically significant concentration range, enabling potential usage of this biosensor for diagnosis of acute myocardial infarction. The real-time response of the sensor to the myoglobin binding may potentially provide point-of-care monitoring of patients and treatment effects.

Photoacoustic emission from fluorescent nanodiamonds enhanced with gold nanoparticles.

Fluorescent nanodiamonds (FNDs) have drawn much attention in recent years for biomedical imaging applications due to their desired physical properties including excellent photostability, high biocompatibility, extended far-red fluorescence emission, and ease of surface functionalization. Here we explore a new feature of FNDs, i.e. their photoacoustic emission capability, which may lead to potential applications of using FNDs as a dual imaging contrast agent for combined fluorescence and photoacoustic imaging modalities. We observed significant enhancement of photoacoustic emission from FNDs when they were conjugated with gold nanoparticles (GNPs).

Detection of anthrax lef with DNA-based photonic crystal sensors.

Bacillus anthracis has posed a threat of becoming biological weapons of mass destruction due to its virulence factors encoded by the plasmid-borne genes, such as lef for lethal factor. We report the development of a fast and sensitive anthrax DNA biosensor based on a photonic crystal structure used in a total-internal-reflection configuration. For the detection of the lef gene, a single-stranded DNA lef probe was biotinylated and immobilized onto the sensor via biotin-streptavidin interactions. A positive control, lef-com, was the complementary strand of the probe, while a negative control was an unrelated single-stranded DNA fragment from the 16S rRNA gene of Acinetobacter baumannii. After addition of the biotinylated lef probe onto the sensor, significant changes in the resonance wavelength of the sensor were observed, resulting from binding of the probe to streptavidin on the sensor. The addition of lef-com led to another significant increase as a result of hybridization between the two DNA strands. The detection sensitivity for the target DNA reached as low as 0.1 nM. In contrast, adding the unrelated DNAs did not cause an obvious shift in the resonant wavelength. These results demonstrate that detection of the anthrax lef by the photonic crystal structure in a total-internal-reflection sensor is highly specific and sensitive.

Impacting obesity and glycemic control using a culturally-sensitive diabetes education program in Hispanic patients with type 2 diabetes.

OBJECTIVES: Diabetes mellitus and obesity are prevalent in the Hispanic community. This group has not benefited greatly from diabetes interventions due to cultural, language and financial constraints. We designed a prospective cohort study to determine the clinical impact on adiposity and glycemic control in Hispanics with type 2 diabetes. RESEARCH DESIGN AND METHODS: The program conducted in Spanish by a multidisciplinary team of health care providers focused on improving glycemic control and complications through cultural lifestyle changes. Outcomes were changes in glycemic control by fasting insulin, glucose and HbA1c, body composition and selected adipokines, adiponectin, leptin and ghrelin. Body composition was measured by dual energy x-ray absorptiometry. Changes from baseline at three months were compared using paired t-tests and with Spearman's correlations. RESULTS: Glycemic control improved by HbA1c (7.9% ± 2.0% vs 7.1% ± 1.7%; P = <0.001), and fasting glucose (166.4 ± 66.0 mg/dl vs 143.2 ± 57.9 mg/dl; P = 0.003). Body weight (81.3 ± 17.9 kg vs 80.3 ± 18.0 kg; P = 0.002), waist circumference (101.6 ± 13.4 cm vs 99.1 ± 12.7 cm; P = 0.015), and truncal fat (16.5 ± 5.7 kg vs 15.9 ± 5.6 kg; P = 0.001) decreased. Only leptin (19.6 ± 15.0 ng/ml vs 16.3 ± 12.7 ng/ml; P = 0.002) was reduced and related to change in body weight (r = 0.392; P = 0.022). CONCLUSIONS: Our program significantly improved glycemic control and decreased obesity in diabetic Hispanic subjects. The early benefits on glycemic control may be related to reductions in leptin through loss of adipose tissue. Success in impacting diabetes and related complications can occur in a culturally focused and multidisciplinary context.

Long-term survival with ACTH-secreting carcinoma of the pituitary: a case report and review of the literature.

A 48-yr-old woman was evaluated 21 yr after receiving treatment for an ACTH-secreting metastatic pituitary carcinoma. She had been diagnosed with Cushing's disease 35 yr earlier at the age of 14 yr and had undergone bilateral adrenalectomy. Six years later she developed Nelson's syndrome, which was treated with resection of a pituitary adenoma followed by radiotherapy to the sella turcica. Eight years later she was found to have craniospinal metastases with three remote intracerebral lesions. Two of these lesions were surgically resected and stained positive for ACTH by immunofluorescence. She subsequently received whole-brain radiotherapy and is doing well 21 yr later with no lesions seen on magnetic resonance imaging and no evidence of recurrent metastatic disease. We present this case in detail along with a literature review of ACTH-secreting pituitary carcinoma.