Discharge patterns in the lateral superior olive of decerebrate cats.

Anatomical and pharmacological studies have shown that the lateral superior olive (LSO) receives inputs from a number of sources and that LSO cells can alter the balance of their own excitatory and inhibitory drive. It is thus likely that the ongoing sound-evoked responses of LSO cells reflect a complex interplay of excitatory and inhibitory events, which may be affected by anesthesia. The goal of this study was to characterize the temporal discharge patterns of single units in the LSO of unanesthetized, decerebrate cats in response to long-duration ipsilateral best-frequency tone bursts. A decision tree is presented to partition LSO units on the basis of poststimulus time histogram shape, adaptation of instantaneous firing rate as a function of time, and sustained discharge rate. The results suggest that LSO discharge patterns form a continuum with four archetypes: sustained choppers that show two or more peaks of activity at stimulus onset and little adaptation of rate throughout the response, transient choppers that undergo a decrease in rate that eventually stabilizes with time, primary-like units that display an initial peak of activity followed by a monotonic decline in rate to a steady-state value, and onset-sustained units that exhibit an initial peak of activity at stimulus onset followed by a low sustained activity. Compared with the chopper units, the nonchopper units tend to show longer first-spike latencies, lower peak firing rates, and more irregular sustained discharge patterns. Modeling studies show that the full range of LSO response types can be obtained from an underlying sustained chopper by varying the strength and latency of a sound-driven ipsilateral inhibition relative to that of excitation. Together, these results suggest that inhibition plays a major role in shaping the temporal discharge patterns of units in unanesthetized preparations.

Combustion of C1 and C2 PFAS: Kinetic modeling and experiments.

A combustion model, originally developed to simulate the destruction of chemical warfare agents, was modified to include C1-C3 fluorinated organic reactions and kinetics compiled by the National Institute of Standards and Technology (NIST). A simplified plug flow reactor version of this model was used to predict the destruction efficiency (DE) and formation of products of incomplete combustion (PICs) for three C1 and C2 per- and poly-fluorinated alkyl substances (PFAS) (CF4, CHF3, and C2F6) and compare predicted values to Fourier Transform Infrared spectroscopy (FTIR)-based measurements made from a pilot-scale EPA research combustor (40-64 kW, natural gas-fired, 20% excess air). PFAS were introduced through the flame, and at post-flame locations along a time-temperature profile allowing for simulation of direct flame and non-flame injection, and examination of the sensitivity of PFAS destruction on temperature and free radical flame chemistry. Results indicate that CF4 is particularly difficult to destroy with DEs ranging from ~60 to 95% when introduced through the flame at increasing furnace loads. Due to the presence of lower energy C-H and C-C bonds to initiate molecular dissociation reactions, CHF3 and C2F6 were easier to destroy, exhibiting DEs >99% even when introduced post-flame. However, these lower bond energies may also lead to the formation of CF2 and CF3 radicals at thermal conditions unable to fully de-fluorinate these species and formation of fluorinated PICs. DEs determined by the model agreed well with the measurements for CHF3 and C2F6 but overpredicted DEs at high temperatures and underpredicted DEs at low temperatures for CF4. However, high DEs do not necessarily mean absence of PICs, with both model predictions and limited FTIR measurements indicating the presence of similar fluorinated PICs in the combustion emissions. The FTIR was able to provide real-time emission measurements and additional model development may improve prediction of PFAS destruction and PIC formation.Implications: The widespread use of PFAS for over 70 years has led to their presence in multiple environmental matrixes including human tissues. While the chemical and thermal stability of PFAS are related to their desirable properties, this stability means that PFAS are very slow to degrade naturally and potentially difficult to destroy completely through thermal treatment processes often used for organic waste destruction. In this applied combustion study, model PFAS compounds were introduced to a pilot-scale EPA research furnace. Real-time FTIR measurements were performed of the injected compound and trace products of incomplete combustion (PICs) at operationally relevant conditions, and the results were successfully compared to kinetic model predictions of those same PFAS destruction efficiencies and trace gas-phase PIC constituents. This study represents a significant potential enhancement in available tools to support effective management of PFAS-containing wastes.

Somatosensory context alters auditory responses in the cochlear nucleus.

The cochlear nucleus, the first central auditory structure, performs initial stimulus processing and segregation of information into parallel ascending pathways. It also receives nonauditory inputs. Here we show in vivo that responses of dorsal cochlear nucleus (DCN) principal neurons to sounds can change significantly depending on the presence or absence of inputs from the somatosensory dorsal column nucleus occurring before the onset of auditory stimuli. The effects range from short-term suppression of spikes lasting a few milliseconds at the onset of the stimulus to long-term increases or decreases in spike rate that last throughout the duration of an acoustic stimulus (up to several hundred milliseconds). The long-term effect requires only a single electrical stimulus pulse to initiate and seems to be similar to persistent activity reported in other parts of the brain. Among the DCN inhibitory interneurons, only the cartwheel cells show a long-term rate decrease that could account for the rate increases (but not the decreases) of DCN principal cells. Thus even at the earliest stages of auditory processing, the represented information is dependent on nonauditory context, in this case somatosensory events.

On the role of the wideband inhibitor in the dorsal cochlear nucleus: a computational modeling study.

Principal cells (type IV units) in the dorsal cochlear nucleus (DCN) are uniquely sensitive to (are inhibited by) energy minima or notches in acoustic spectra, which provide cues to sound localization. The once accepted conceptual model of the DCN suggested that this sensitivity was shaped largely by inhibitory inputs from wideband inhibitors (WBIs), which received auditory nerve inputs over a wide frequency range and inhibited type IV units over a narrow frequency range. A computational model based on this wide-input narrow-output conceptual model was able to reproduce quantitatively type IV unit responses to notch-noise stimuli as a function of notch width. Recent physiological results have shown however that WBIs are unresponsive to notch-noise stimuli with wide notch widths and thus have narrower auditory nerve fiber input bandwidths than previously assumed. A computational model based on a narrow-input narrow-output model of the WBI was unable to account fully for the notch sensitivity of type IV units suggesting the need to add a new component to the DCN circuit. The goal of this study was to test whether making the output bandwidth of the WBIs wide while keeping their input bandwidth narrow could explain the responses of type IV units to notch-noise stimuli. Anatomical evidence supports this model configuration, and the results show that such a model can produce strong inhibition in type IV units for wide notches. The results thus suggest that WBIs, in narrow-input wide-output form, are sufficient to account for the notch sensitivity of DCN type IV units.

Contralateral effects and binaural interactions in dorsal cochlear nucleus.

The dorsal cochlear nucleus (DCN) receives afferent input from the auditory nerve and is thus usually thought of as a monaural nucleus, but it also receives inputs from the contralateral cochlear nucleus as well as descending projections from binaural nuclei. Evidence suggests that some of these commissural and efferent projections are excitatory, whereas others are inhibitory. The goals of this study were to investigate the nature and effects of these inputs in the DCN by measuring DCN principal cell (type IV unit) responses to a variety of contralateral monaural and binaural stimuli. As expected, the results of contralateral stimulation demonstrate a mixture of excitatory and inhibitory influences, although inhibitory effects predominate. Most type IV units are weakly, if at all, inhibited by tones but are strongly inhibited by broadband noise (BBN). The inhibition evoked by BBN is also low threshold and short latency. This inhibition is abolished and excitation is revealed when strychnine, a glycine-receptor antagonist, is applied to the DCN; application of bicuculline, a GABAA-receptor antagonist, has similar effects but does not block the onset of inhibition. Manipulations of discrete fiber bundles suggest that the inhibitory, but not excitatory, inputs to DCN principal cells enter the DCN via its output pathway, and that the short latency inhibition is carried by commissural axons. Consistent with their respective monaural effects, responses to binaural tones as a function of interaural level difference are essentially the same as responses to ipsilateral tones, whereas binaural BBN responses decrease with increasing contralateral level. In comparison to monaural responses, binaural responses to virtual space stimuli show enhanced sensitivity to the elevation of a sound source in ipsilateral space but reduced sensitivity in contralateral space. These results show that the contralateral inputs to the DCN are functionally relevant in natural listening conditions, and that one role of these inputs is to enhance DCN processing of spectral sound localization cues produced by the pinna.

Auditory processing of spectral cues for sound localization in the inferior colliculus.

The head-related transfer function (HRTF) of the cat adds directionally dependent energy minima to the amplitude spectrum of complex sounds. These spectral notches are a principal cue for the localization of sound source elevation. Physiological evidence suggests that the dorsal cochlear nucleus (DCN) plays a critical role in the brainstem processing of this directional feature. Type O units in the central nucleus of the inferior colliculus (ICC) are a primary target of ascending DCN projections and, therefore, may represent midbrain specializations for the auditory processing of spectral cues for sound localization. Behavioral studies confirm a loss of sound orientation accuracy when DCN projections to the inferior colliculus are surgically lesioned. This study used simple analogs of HRTF notches to characterize single-unit response patterns in the ICC of decerebrate cats that may contribute to the directional sensitivity of the brain's spectral processing pathways. Manipulations of notch frequency and bandwidth demonstrated frequency-specific excitatory responses that have the capacity to encode HRTF-based cues for sound source location. These response patterns were limited to type O units in the ICC and have not been observed for the projection neurons of the DCN. The unique spectral integration properties of type O units suggest that DCN influences are transformed into a more selective representation of sound source location by a local convergence of wideband excitatory and frequency-tuned inhibitory inputs.

Decreased cortical gray and cerebral white matter in male patients with familial bipolar I disorder.

BACKGROUND: Previous MRI studies of bipolar disorder have failed to consistently demonstrate cortical gray or cerebral white matter tissue loss, as well as sulcal or ventricular enlargement. The inconsistencies are most likely due to the clinical and gender heterogeneity of the study populations as well as the different MRI acquisition and processing techniques. The objective of this study was to determine if there was a cortical gray matter and cerebral white matter deficit as well as sulcal and ventricular enlargement in a homogeneous sample of euthymic male patients with familial bipolar I disorder. METHODS: MRI tissue segmentation was utilized to obtain cortical gray matter, cerebral white matter, ventricular cerebrospinal fluid (CSF), and sulcal CSF volumes in 22 euthymic males with familial bipolar I disorder and 32 healthy male control subjects. RESULTS: Relative to the controls, the familial bipolar I patients demonstrated: (1) significant reductions of both cortical gray matter and cerebral white matter volumes; and (2) significant increases in both sulcal and ventricular CSF volumes. In the bipolar group, there was a significant negative correlation between cortical gray matter volume and sulcal CSF volume. LIMITATIONS: Small sample size, retrospective interviews, possible medication effects. CONCLUSIONS: These results provide evidence for significant cortical gray matter and cerebral white matter deficits and associated sulcal and ventricular enlargement in euthymic males with familial bipolar I disorder.

The focal adhesion-localized CdGAP regulates matrix rigidity sensing and durotaxis.

Motile cells are capable of sensing the stiffness of the surrounding extracellular matrix through integrin-mediated focal adhesions and migrate towards regions of higher rigidity in a process known as durotaxis. Durotaxis plays an important role in normal development and disease progression, including tumor invasion and metastasis. However, the signaling mechanisms underlying focal adhesion-mediated rigidity sensing and durotaxis are poorly understood. Utilizing matrix-coated polydimethylsiloxane gels to manipulate substrate compliance, we show that cdGAP, an adhesion-localized Rac1 and Cdc42 specific GTPase activating protein, is necessary for U2OS osteosarcoma cells to coordinate cell shape changes and migration as a function of extracellular matrix stiffness. CdGAP regulated rigidity-dependent motility by controlling membrane protrusion and adhesion dynamics, as well as by modulating Rac1 activity. CdGAP was also found to be necessary for U2OS cell durotaxis. Taken together, these data identify cdGAP as an important component of an integrin-mediated signaling pathway that senses and responds to mechanical cues in the extracellular matrix in order to coordinate directed cell motility.

Dynamic cell behavior on shape memory polymer substrates.

Cell culture substrates of defined topography have emerged as powerful tools with which to investigate cell mechanobiology, but current technologies only allow passive control of substrate properties. Here we present a thermo-responsive cell culture system that uses shape memory polymer (SMP) substrates that are programmed to change surface topography during cell culture. Our hypothesis was that a shape-memory-activated change in substrate topography could be used to control cell behavior. To test this hypothesis, we embossed an initially flat SMP substrate to produce a temporary topography of parallel micron-scale grooves. After plating cells on the substrate, we triggered shape memory activation using a change in temperature tailored to be compatible with mammalian cell culture, thereby causing topographic transformation back to the original flat surface. We found that the programmed erasure of substrate topography caused a decrease in cell alignment as evidenced by an increase in angular dispersion with corresponding remodeling of the actin cytoskeleton. Cell viability remained greater than 95% before and after topography change and temperature increase. These results demonstrate control of cell behavior through shape-memory-activated topographic changes and introduce the use of active cell culture SMP substrates for investigation of mechanotransduction, cell biomechanical function, and cell soft-matter physics.

Shape memory polymers for active cell culture.

Shape memory polymers (SMPs) are a class of "smart" materials that have the ability to change from a fixed, temporary shape to a pre-determined permanent shape upon the application of a stimulus such as heat(1-5). In a typical shape memory cycle, the SMP is first deformed at an elevated temperature that is higher than its transition temperature, T(trans;) [either the melting temperature (T(m;)) or the glass transition temperature (T(g;))]. The deformation is elastic in nature and mainly leads to a reduction in conformational entropy of the constituent network chains (following the rubber elasticity theory). The deformed SMP is then cooled to a temperature below its T(trans;) while maintaining the external strain or stress constant. During cooling, the material transitions to a more rigid state (semi-crystalline or glassy), which kinetically traps or "freezes" the material in this low-entropy state leading to macroscopic shape fixing. Shape recovery is triggered by continuously heating the material through T(trans;) under a stress-free (unconstrained) condition. By allowing the network chains (with regained mobility) to relax to their thermodynamically favored, maximal-entropy state, the material changes from the temporary shape to the permanent shape. Cells are capable of surveying the mechanical properties of their surrounding environment(6). The mechanisms through which mechanical interactions between cells and their physical environment control cell behavior are areas of active research. Substrates of defined topography have emerged as powerful tools in the investigation of these mechanisms. Mesoscale, microscale, and nanoscale patterns of substrate topography have been shown to direct cell alignment, cell adhesion, and cell traction forces(7-14). These findings have underscored the potential for substrate topography to control and assay the mechanical interactions between cells and their physical environment during cell culture, but the substrates used to date have generally been passive and could not be programmed to change significantly during culture. This physical stasis has limited the potential of topographic substrates to control cells in culture. Here, active cell culture (ACC) SMP substrates are introduced that employ surface shape memory to provide programmed control of substrate topography and deformation. These substrates demonstrate the ability to transition from a temporary grooved topography to a second, nearly flat memorized topography. This change in topography can be used to control cell behavior under standard cell culture conditions.

Monaural spectral processing differs between the lateral superior olive and the inferior colliculus: physiological evidence for an acoustic chiasm.

Evidence suggests that the lateral superior olive (LSO) initiates an excitatory pathway specialized to process interaural level differences (ILDs), the primary cues used by mammals to localize high-frequency sounds in the horizontal plane. Type I units in the central nucleus of the inferior colliculus (ICC) of decerebrate cats exhibit monaural and binaural response properties qualitatively similar to those of LSO units, and are thus supposed to be the midbrain component of the ILD pathway. Studies have shown, however, that the responses of ICC cells do not often reflect simply the output of any single source of excitatory inputs. The goal of this study was to compare directly the monaural, spectral response properties of LSO and type I units measured in unanesthetized decerebrate cats. Compared to LSO units, type I units have narrower V-shaped excitatory tuning curves, higher spontaneous rates, lower maximum stimulus-evoked firing rates and more nonmonotonic rate-level curves for tones and noise. In addition, low-frequency type I units have lower thresholds to tones than corresponding LSO units. Taken together, these results suggest that the excitatory ILD pathway from LSO to ICC is mostly a high-frequency channel, and that additional inputs transform LSO influences in the ICC.

High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus.

CONTEXT: Cross-sectional epidemiological studies have found that patients with type 2 diabetes mellitus (T2DM) have a higher incidence of certain fragility fractures despite normal or elevated bone mineral density (BMD). OBJECTIVE: In this study, high-resolution peripheral quantitative computed tomography was applied to characterize cortical and trabecular microarchitecture and biomechanics in the peripheral skeleton of female patients with T2DM. DESIGN AND SETTING: A cross-sectional study was conducted in patients with T2DM recruited from a diabetic outpatient clinic. PARTICIPANTS: Elderly female patients (age, 62.9 ± 7.7 yr) with a history of T2DM (n = 19) and age- and height-matched controls (n = 19) were recruited. OUTCOME MEASURES: Subjects were imaged using high-resolution peripheral quantitative computed tomography at the distal radius and tibia. Quantitative measures of volumetric (BMD), cross-sectional geometry, trabecular and cortical microarchitecture were calculated. Additionally, compressive mechanical properties were determined by micro-finite element analysis. RESULTS: Compared to the controls, the T2DM cohort had 10% higher trabecular volumetric BMD (P < 0.05) adjacent to the cortex and higher trabecular thickness in the tibia (13.8%; P < 0.05). Cortical porosity differences alone were consistent with impaired bone strength and were significant in the radius (>+50%; P < 0.05), whereas pore volume approached significance in the tibia (+118%; P = 0.1). CONCLUSION: The results of this pilot investigation provide a potential explanation for the inability of standard BMD measures to explain the elevated fracture incidence in patients with T2DM. The findings suggest that T2DM may be associated with impaired resistance to bending loads due to inefficient redistribution of bone mass, characterized by loss of intracortical bone offset by an elevation in trabecular bone density.

Response properties of single units in the dorsal nucleus of the lateral lemniscus of decerebrate cats.

The dorsal nucleus of the lateral lemniscus (DNLL) receives afferent inputs from many brain stem nuclei and, in turn, is a major source of inhibitory inputs to the inferior colliculus (IC). The goal of this study was to characterize the monaural and binaural response properties of neurons in the DNLL of unanesthetized decerebrate cat. Monaural responses were classified according to the patterns of excitation and inhibition observed in contralateral and ipsilateral frequency response maps. Binaural classification was based on unit sensitivity to interaural level differences. The results show that units in the DNLL can be grouped into three distinct types. Type v units produce contralateral response maps that show a wide V-shaped excitatory area and no inhibition. These units receive ipsilateral excitation and exhibit binaural facilitation. The contralateral maps of type i units show a more restricted I-shaped region of excitation that is flanked by inhibition. Type o maps display an O-shaped island of excitation at low stimulus levels that is bounded by inhibition at higher levels. Both type i and type o units receive ipsilateral inhibition and exhibit binaural inhibition. Units that produce type v maps have a low best frequency (BF), whereas type i and type o units have high BFs. Type v and type i units give monotonic rate-level responses for both BF tones and broadband noise. Type o units are inhibited by tones at high levels, but are excited by high-level noise. These results show that the DNLL can exert strong, differential effects in the IC.

The effects of geometric and threshold definitions on cortical bone metrics assessed by in vivo high-resolution peripheral quantitative computed tomography.

This study evaluates in vivo methods for calculating cortical thickness (Ct.Th) with respect to sensitivity to tissue-level changes in mineralization and the ability to predict whole-bone mechanical properties. Distal radial and tibial images obtained from normal volunteers using high-resolution peripheral quantitative computed tomography (HR-pQCT) were segmented using three thresholds including the manufacturer default and +/-5% in terms of equivalent mineral density. Ct.Th was determined in two ways: using a direct three-dimensional (3D) method and using an annular method, where cortical bone volume is divided by periosteal surface area. D(comp) (mg HA/cm(3)) was calculated based on the mean density-calibrated linear attenuation values of the cortical compartment. Finite element analysis was performed to evaluate the predictive ability of the annular and direct Ct.Th methods. Using the direct 3D method, a +/-5% change in threshold resulted in a 2% mean difference in Ct.Th for both the radius and tibia. An average difference of 5% was found using the annular method. The change in threshold produced changes in D(comp) ranging 0.50-1.56% for both the tibia and radius. Annular Ct.Th correlated more strongly with whole-bone apparent modulus (R(2)=0.64 vs. R(2)=0.41). Both thickness calculation methods and threshold selection have a direct impact on cortical parameters derived from HR-pQCT images. Indirectly, these results suggest that moderate changes in tissue-level mineralization can affect cortical measures. Furthermore, while the direct 3D Ct.Th method is less sensitive to threshold effects, both methods are moderate predictors of mechanical strength, with the annular method being the stronger correlate.

Evidence of a functionally segregated pathway from dorsal cochlear nucleus to inferior colliculus.

Type O units in the central nucleus of the inferior colliculus (ICC) of decerebrate cats are excited by best frequency (BF) tones near threshold, but are inhibited by high-level tones at all frequencies. Dorsal cochlear nucleus (DCN) principal cells display similar response map features and project directly to the ICC, and are thus supposed to be the dominant source of excitatory input for type O units. To test this hypothesis, the responses of type O units were compared before and after two pharmacological manipulations. When DCN to ICC axons were blocked by pressure injections of lidocaine, most type O units (approximately 80%) were silenced or showed substantially reduced activity, but some units showed increased activity. All of the former units had low maximal rates to BF tones, whereas the latter units had high rates. When local circuit inhibitory mechanisms in the ICC were blocked by iontophoretic application of bicuculline or strychnine, type O unit responses also fell into two classes: low-rate units that showed increased spontaneous and driven activities and high-rate units that showed, in addition, altered response map features. Taken together, these results demonstrate that low-rate type O units are part of a functionally segregated pathway initiated by the DCN, whereas high-rate type O units are created at the level of the ICC.