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1.  Thalamocortical Projections to Rat Auditory Cortex From the Ventral and Dorsal Divisions of the Medial Geniculate Nucleus 
The ventral and dorsal medial geniculate (MGV and MGD) constitute the major auditory thalamic subdivisions providing thalamocortical inputs to layer IV and lower layer III of auditory cortex. No quantitative evaluation of this projection is available. Using biotinylated dextran amine (BDA)/biocytin injections, we describe the cortical projection patterns of MGV and MGD cells. In primary auditory cortex the bulk of MGV axon terminals are in layer IV/lower layer III with minor projections to supragranular layers and intermediate levels in infragranular layers. MGD axons project to cortical regions designated posterodorsal (PD) and ventral (VA) showing laminar terminal distributions that are quantitatively similar to the MGV-to-primary cortex terminal distribution. At the electron microscopic level MGV and MGD terminals are non-γ-aminobutyric acid (GABA)ergic with MGD terminals in PD and VA slightly but significantly larger than MGV terminals in primary cortex. MGV/MGD terminals synapse primarily onto non-GABAergic spines/dendrites. A small number synapse on GABAergic structures, contacting large dendrites or cell bodies primarily in the major thalamocortical recipient layers. For MGV projections to primary cortex or MGD projections to PD or VA, the non-GABAergic post-synaptic structures at each site were the same size regardless of whether they were in supragranular, granular, or infragranular layers. However, the population of MGD terminal-recipient structures in VA were significantly larger than the MGD terminal-recipient structures in PD or the MGV terminal-recipient structures in primary cortex. Thus, if terminal and postsynaptic structure size indicate strength of excitation then MGD to VA inputs are strongest, MGD to PD intermediate, and MGV to primary cortex the weakest.
PMCID: PMC3320111  PMID: 21618239
electron microscopy; GABA; medial geniculate nucleus
2.  Marijuana withdrawal and aggression among a representative sample of U.S. marijuana users 
Drug and alcohol dependence  2013;132(0):63-68.
Previous laboratory-based research suggests that withdrawal from marijuana may cause increased aggression. It is unclear whether this finding extends beyond the laboratory setting to the general population of marijuana users. The purpose of this study was to test a cross-sectional association between marijuana withdrawal symptoms and aggression among a representative sample of U.S. adult marijuana users, and to test whether this association was moderated by previous history of aggression.
Data were analyzed from the National Epidemiologic Survey on Alcohol and Related Conditions. Wave Two data (2004–2005) were used for all variables except for history of aggression, which was assessed during the Wave One interview (2001–2002). Two outcomes were examined: self-report general aggression and relationship aggression. Odds ratios for aggression based on withdrawal symptoms and the interaction between withdrawal symptoms and history of aggression were calculated using logistic regression, adjusting for covariates and accounting for the complex survey design.
Among marijuana users with a history of aggression, marijuana withdrawal was associated with approximately 60% higher odds of past year relationship aggression (p < 0.05). There was no association between withdrawal symptoms and relationship aggression among those without a history of aggression, and no association with general aggression regardless of history of aggression.
The findings from this study support the notion that laboratory-based increases in aggression due to marijuana withdrawal extend to the general population of marijuana users who have a previous history of aggression.
PMCID: PMC3706470  PMID: 23380439
marijuana; withdrawal; aggression; cannabis; THC; NESARC
3.  Intimate partner violence and specific substance use disorders: Findings from the National Epidemiologic Survey on Alcohol and Related Conditions 
The association between substance use and intimate partner violence (IPV) is robust. It is less clear how the use of specific substances relates to relationship violence. This study examined IPV perpetration and victimization related to the following specific substance use disorders: alcohol, cannabis, cocaine and opioid. The poly-substance use of alcohol and cocaine, as well as alcohol and marijuana were also examined. Data were analyzed from wave two of the National Epidemiologic Study on Alcohol and Related Conditions (2004–2005). Associations between substance use disorders and IPV were tested using logistic regression models while controlling for important covariates and accounting for the complex survey design. Alcohol use disorders and cocaine use disorders were most strongly associated with IPV perpetration, while cannabis use disorders and opioid use disorders were most strongly associated with IPV victimization. A diagnosis of both an alcohol use disorder and cannabis use disorder decreased the likelihood of IPV perpetration compared to each individual substance use disorder. A diagnosis of both an alcohol use disorder and cocaine use disorder increased likelihood of reporting IPV perpetration compared to alcohol use disorders alone, but decreased likelihood of perpetration compared to a cocaine use disorder diagnosis alone. Overall, substance use disorders were consistently related to intimate partner violence after controlling for important covariates. These results provide further evidence for the important link between substance use disorders and IPV, and add to our knowledge of which specific substances may be related to relationship violence.
PMCID: PMC3883081  PMID: 21823768
Intimate partner violence; substance use; mental health; alcohol use; illicit drug use
4.  Spiking in auditory cortex following thalamic stimulation is dominated by cortical network activity 
The state of the sensory cortical network can have a profound impact on neural responses and perception. In rodent auditory cortex, sensory responses are reported to occur in the context of network events, similar to brief UP states, that produce “packets” of spikes and are associated with synchronized synaptic input (Bathellier et al., 2012; Hromadka et al., 2013; Luczak et al., 2013). However, traditional models based on data from visual and somatosensory cortex predict that ascending sensory thalamocortical (TC) pathways sequentially activate cells in layers 4 (L4), L2/3, and L5. The relationship between these two spatio-temporal activity patterns is unclear. Here, we used calcium imaging and electrophysiological recordings in murine auditory TC brain slices to investigate the laminar response pattern to stimulation of TC afferents. We show that although monosynaptically driven spiking in response to TC afferents occurs, the vast majority of spikes fired following TC stimulation occurs during brief UP states and outside the context of the L4>L2/3>L5 activation sequence. Specifically, monosynaptic subthreshold TC responses with similar latencies were observed throughout layers 2–6, presumably via synapses onto dendritic processes located in L3 and L4. However, monosynaptic spiking was rare, and occurred primarily in L4 and L5 non-pyramidal cells. By contrast, during brief, TC-induced UP states, spiking was dense and occurred primarily in pyramidal cells. These network events always involved infragranular layers, whereas involvement of supragranular layers was variable. During UP states, spike latencies were comparable between infragranular and supragranular cells. These data are consistent with a model in which activation of auditory cortex, especially supragranular layers, depends on internally generated network events that represent a non-linear amplification process, are initiated by infragranular cells and tightly regulated by feed-forward inhibitory cells.
PMCID: PMC4168681  PMID: 25285071
auditory cortex; thalamo-cortical (TC); UP states; canonical microcircuit; calcium imaging; multiunit activity; patch clamp
6.  Descending Projections from Extrastriate Visual Cortex Modulate Responses of Cells in Primary Auditory Cortex 
Cerebral Cortex (New York, NY)  2011;21(11):2620-2638.
Primary sensory cortical responses are modulated by the presence or expectation of related sensory information in other modalities, but the sources of multimodal information and the cellular locus of this integration are unclear. We investigated the modulation of neural responses in the murine primary auditory cortical area Au1 by extrastriate visual cortex (V2). Projections from V2 to Au1 terminated in a classical descending/modulatory pattern, with highest density in layers 1, 2, 5, and 6. In brain slices, whole-cell recordings revealed long latency responses to stimulation in V2L that could modulate responses to subsequent white matter (WM) stimuli at latencies of 5–20 ms. Calcium responses imaged in Au1 cell populations showed that preceding WM with V2L stimulation modulated WM responses, with both summation and suppression observed. Modulation of WM responses was most evident for near-threshold WM stimuli. These data indicate that corticocortical projections from V2 contribute to multimodal integration in primary auditory cortex.
PMCID: PMC3183425  PMID: 21471557
calcium imaging; cortical column; layer 5; neocortex; patch clamping
7.  Axonal branching patterns as sources of delay in the mammalian auditory brainstem: a reexamination 
In models of temporal processing, time delays incurred by axonal propagation of action potentials play a prominent role. A preeminent model of temporal processing in audition is the binaural model of Jeffress (1948), which has dominated theories regarding our acute sensitivity to interaural time differences (ITDs). In Jeffress’ model a binaural cell is maximally active when the ITD is compensated by an internal delay, which brings the inputs from left and right ears in coincidence, and which would arise from axonal branching patterns of monaural input fibers. By arranging these patterns in systematic and opposite ways for the ipsi- and contralateral inputs, a range of length differences, and thereby of internal delays, is created so that ITD is transformed into a spatial activation pattern along the binaural nucleus. We reanalyze single, labeled and physiologically characterized, axons of spherical bushy cells of the cat anteroventral cochlear nucleus (AVCN) which project to binaural coincidence detectors in the medial superior olive (MSO). The reconstructions largely confirm the observations of two previous reports, but several features are observed which are inconsistent with Jeffress’ model. We found that ipsilateral projections can also form a caudally-directed delay line pattern, which would counteract delays incurred by caudally-directed contralateral projections. Comparisons of estimated axonal delays with binaural physiological data indicate that the suggestive anatomical patterns cannot account for the frequency-dependent distribution of best delays in the cat. Surprisingly, the tonotopic distribution of the afferents endings indicate that low CFs are under- rather than overrepresented in the MSO.
PMCID: PMC3157295  PMID: 21414923
8.  A unique combination of anatomy and physiology in cells of the rat paralaminar thalamic nuclei adjacent to the medial geniculate body 
The medial geniculate body (MGB) has three major subdivisions - ventral (MGV), dorsal (MGD) and medial (MGM). MGM is linked with paralaminar nuclei that are situated medial and ventral to MGV/MGD. Paralaminar nuclei have unique inputs and outputs when compared with MGV and MGD and have been linked to circuitry underlying some important functional roles. We recorded intracellularly from cells in the paralaminar nuclei in vitro. We found that they possess an unusual combination of anatomical and physiological features when compared to those reported for “standard” thalamic neurons seen in the MGV/MGD and elsewhere in the thalamus. Compared to MGV/MGD neurons, anatomically, 1) paralaminar cell dendrites can be long, branch sparingly and encompass a much larger area. 2) their dendrites may be smooth but can have well defined spines and 3) their axons can have collaterals that branch locally within the same or nearby paralaminar nuclei. When compared to MGV/MGD neurons physiologically 1) their spikes are larger in amplitude and can be shorter in duration and 2) can have dual afterhyperpolarizations with fast and slow components and 3) they can have a reduction or complete absence of the low threshold, voltage-sensitive calcium conductance that reduces or eliminates the voltage-dependent burst response. We also recorded from cells in the parafascicular nucleus, a nucleus of the posterior intralaminar nuclear group, because they have unusual anatomical features that are similar to some of our paralaminar cells. Like the labeled paralaminar cells, parafascicular cells had physiological features distinguishing them from typical thalamic neurons.
PMCID: PMC2943380  PMID: 16566009
calcium burst; intralaminar nuclei; parafascicular nucleus
9.  The Volley theory and the Spherical Cell puzzle 
Neuroscience  2008;154(1):65-76.
Temporal coding in the auditory nerve is strikingly transformed in the cochlear nucleus. In contrast to fibers in the auditory nerve, some neurons in the cochlear nucleus can show “picket fence” phase-locking to low-frequency pure tones: they fire a precisely timed action potential at every cycle of the stimulus. Such synchronization enhancement and entrainment is particularly prominent in neurons with the spherical and globular morphology, described by Osen (1969). These neurons receive large axosomatic terminals from the auditory nerve - the endbulbs and modified endbulbs of Held - and project to binaural comparator nuclei in the superior olivary complex. The most popular model to account for picket fence phase-locking is monaural coincidence detection. This mechanism is plausible for globular neurons, which receive a large number of inputs. We draw attention to the existence of enhanced phase-locking and entrainment in spherical neurons, which receive too few endbulb inputs from the auditory nerve to make a coincidence detection of endbulb firings a plausible mechanism of synchronization enhancement.
PMCID: PMC2486254  PMID: 18424004
temporal coding; binaural; synchronization; amplitude modulation; cochlear nucleus; jitter
10.  Distribution and Kinetic Properties of GABAergic Inputs to Layer V Pyramidal Cells in Rat Auditory Cortex  
Neocortical layer V is distinguished by both its pyramidal cells and its varied cortical and extracortical projections. Several studies suggest that the layer V pyramidal cell types, intrinsically bursting (IB) and regular spiking (RS) cells, differ both in the circuits in which they participate and in their inhibitory inputs. We quantified differences in inhibitory inputs to RS and IB cells using whole-cell voltage clamp techniques in the auditory cortex. We recorded miniature inhibitory postsynaptic currents (mIPSCs) and spontaneous IPSCs to gain kinetic, amplitude, and frequency information about GABAergic synapses. We then used focal sucrose applications to elicit mIPSC rate increases at the soma or dendrites of both cell types. We also electrically stimulated the axons giving rise to inhibitory synaptic inputs to measure minimally evoked IPSCs occurring at the soma or apical dendrites. We found that spontaneous and evoked IPSCs recorded from the auditory cortex have faster rise and decay kinetics when directly compared with those of the same layer V cells in other sensory cortical areas. We also found that mIPSCs observed in auditory IB and RS cells are different from one another. RS cell mIPSCs are larger and have faster rises and decays than IB cell mIPSCs, but IB cell mIPSCs occur more frequently. Focal sucrose application showed that most IB cell mIPSCs originate in the dendrites and are subject to dendritic filtering while most RS cell mIPSCs originate at the soma and are not filtered. These findings suggest that, first, IB and RS cells process their inputs in fundamentally different ways and, second, auditory cortical RS and IB cells may have specializations that allow them to process inhibitory inputs faster.
PMCID: PMC3202454  PMID: 12209293
12.  Address in Medicine 
British Medical Journal  1900;2(2066):280-284.
PMCID: PMC2463287  PMID: 20759136

Results 1-12 (12)