Reduced motor cortex GABABR function following chronic alcohol exposure.

The GABAB receptor (GABABR) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABABR dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABABR-mediated currents, as well as a decrease of GABAB1/2R and G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) activities in the motor cortex. Moreover, our data indicated that these alterations could be attributed to dephosphorylation at the site of serine 783 (ser-783) in GABAB2 subunit, which regulates the surface expression of GABABR. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABABR in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABABR function. The ability to promote GABABR signaling may account for the therapeutic efficacy of baclofen in AUD.

Functional differentiation in the human ventromedial frontal lobe: A data-driven parcellation.

Ventromedial regions of the frontal lobe (vmFL) are thought to play a key role in decision-making and emotional regulation. However, aspects of this area's functional organization, including the presence of a multiple subregions, their functional and anatomical connectivity, and the cross-species homologies of these subregions with those of other species, remain poorly understood. To address this uncertainty, we employed a two-stage parcellation of the region to identify six distinct structures within the region on the basis of data-driven classification of functional connectivity patterns obtained using the meta-analytic connectivity modeling (MACM) approach. From anterior to posterior, the derived subregions included two lateralized posterior regions, an intermediate posterior region, a dorsal and ventral central region, and a single anterior region. The regions were characterized further by functional connectivity derived using resting-state fMRI and functional decoding using the Brain Map database. In general, the regions could be differentiated on the basis of different patterns of functional connectivity with canonical "default mode network" regions and/or subcortical regions such as the striatum. Together, the findings suggest the presence of functionally distinct neural structures within vmFL, consistent with data from experimental animals as well prior demonstrations of anatomical differences within the region. Detailed correspondence with the anterior cingulate, medial orbitofrontal cortex, and rostroventral prefrontal cortex, as well as specific animal homologs are discussed. The findings may suggest future directions for resolving potential functional and structural correspondence of subregions within the frontal lobe across behavioral contexts, and across mammalian species.

Inhibitory Modulation of Orbitofrontal Cortex on Medial Prefrontal Cortex-Amygdala Information Flow.

The amygdala receives cortical inputs from the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) that are believed to affect emotional control and cue-outcome contingencies, respectively. Although mPFC impact on the amygdala has been studied, how the OFC modulates mPFC-amygdala information flow, specifically the infralimbic (IL) division of mPFC, is largely unknown. In this study, combined in vivo extracellular single-unit recordings and pharmacological manipulations were used in anesthetized rats to examine how OFC modulates amygdala neurons responsive to mPFC activation. Compared with basal condition, pharmacological (N-Methyl-D-aspartate) or electrical activation of the OFC exerted an inhibitory modulation of the mPFC-amygdala pathway, which was reversed with intra-amygdala blockade of GABAergic receptors with combined GABAA and GABAB antagonists (bicuculline and saclofen). Moreover, potentiation of the OFC-related pathways resulted in a loss of OFC control over the mPFC-amygdala pathway. These results show that the OFC potently inhibits mPFC drive of the amygdala in a GABA-dependent manner; but with extended OFC pathway activation this modulation is lost. Our results provide a circuit-level basis for this interaction at the level of the amygdala, which would be critical in understanding the normal and pathophysiological control of emotion and contingency associations regulating behavior.

Dopaminergic Modulation of Lateral Amygdala Neuronal Activity: Differential D1 and D2 Receptor Effects on Thalamic and Cortical Afferent Inputs.

BACKGROUND: In auditory fear conditioning, the lateral nucleus of the amygdala (LA) integrates a conditioned stimulus (CS) from the auditory thalamus (MGN) and the auditory association cortex (Te3) with an aversive unconditioned stimulus. The thalamic input provides a basic version of the CS, while the cortical input provides a processed representation of the stimulus. Dopamine (DA) is released in the LA under heightened arousal during the presentation of the CS. METHODS: In this study we examined how D1 or D2 receptor activation affects LA afferent-driven neuronal firing using in vivo extracellular single-unit recordings with local micro-iontophoretic drug application in anesthetized rats. LA neurons that were responsive (~50%) to electrical stimulation in either the MGN or the Te3 were tested by iontophoresis of either the D1 agonist, SKF38393, or the D2 agonist, quinpirole. RESULTS: We found that most of the LA projection neurons exhibited either facilitatory or attenuating effects (changes in evoked probability >15% relative to baseline) on afferent input by activation of D1 or D2 receptors. In general, it required significantly higher stimulation current to evoke ~50% baseline responses to the cortical input. Activation of the D1 receptor showed no difference in modulation between the thalamic or cortical pathways. On the other hand, activation of the D2 receptor had a stronger inhibitory modulation of the cortical pathway, but a stronger excitatory modulation of the thalamic pathway. CONCLUSIONS: Our results suggest that there is a shift in balance favoring the thalamic pathway in response to DA acting via the D2 receptor.

Evidence for impaired sound intensity processing during prepulse inhibition of the startle response in a rodent developmental disruption model of schizophrenia.

A number of studies have implicated disruptions in prepulse inhibition (PPI) of the startle response in both schizophrenia patients and animal models of this disorder. These disruptions are believed to reflect deficits in sensorimotor gating and are ascribed to aberrant filtering of sensory inputs leading to sensory overload and enhanced "noise" in neural structures. Here we examined auditory evoked potentials in a rodent model of schizophrenia (MAM-GD17) during an auditory PPI paradigm to better understand this phenomenon. MAM rats exhibited reductions in specific components of auditory evoked potentials in the orbitofrontal cortex and an abolition of the graded response to stimuli of differing intensities indicating deficient intensity processing in the orbitofrontal cortex. These data indicate that aberrant sensory information processing, rather than being attributable to enhanced noise in neural structures, may be better attributed to diminished evoked amplitudes resulting in a reduction in the "signal-to-noise" ratio. Therefore, the ability for sensory input to modulate the ongoing background activity may be severely disrupted in schizophrenia yielding an internal state which is insufficiently responsive to external input.

The rostral anterior cingulate cortex modulates the efficiency of amygdala-dependent fear learning.

BACKGROUND: The rostral anterior cingulate cortex (rACC) and the amygdala consistently emerge from neuroimaging studies as brain regions crucially involved in normal and abnormal fear processing. To date, however, the role of the rACC specifically during the acquisition of auditory fear conditioning still remains unknown. The aim of this study is to investigate a possible top-down control of a specific rACC sub-region over amygdala activation during pavlovian fear acquisition. METHODS: We performed excitotoxic lesions, temporal inactivation, and activation of a specific sub-region of the rACC that we identified by tracing studies as supporting most of the connectivity with the basolateral amygdala (r(Amy)-ACC). The effects of these manipulations over amygdala function were investigated with a classical tone-shock associative fear conditioning paradigm in the rat. RESULTS: Excitotoxic lesions and transient inactivation of the r(Amy)-ACC pre-training selectively produced deficits in the acquisition of the tone-shock associative learning (but not context). This effect was specific for the acquisition phase. However, the deficit was found to be transient and could be overcome by overtraining. Conversely, pre-training transient activation of the r(Amy)-ACC facilitated associative learning and increased fear expression. CONCLUSIONS: Our results suggest that a subregion of the rACC is key to gating the efficiency of amygdala-dependent auditory fear conditioning learning. Because r(Amy)-ACC inputs were confirmed to be glutamatergic, we propose that recruitment of this brain area might modulate overall basolateral amygdala excitatory tone during conditioned stimulus-unconditioned stimulus concomitant processing. In the light of clinical research, our results provide new insight on the effect of inappropriate rACC recruitment during emotional events.

The Yin and Yang of dopamine release: a new perspective.

Dopamine has undergone extensive investigation due to its known involvement in a number of neurological and psychiatric disorders. In particular, studies into pathological conditions have focused on the roles of high amplitude, phasically evoked dopamine release in regions such as the prefrontal cortex and striatum. However, research has shown that dopamine release can be more complex than just phasic release; thus, there is also a tonic, background dopamine release, with alterations in tonic dopamine release likely having unique and important functional roles. Unfortunately, however, tonic dopamine release has received relatively little attention. In this review, we summarize our recent studies and discuss how modulation of the dopamine system, both in terms of phasic activation and attenuation of tonic dopamine are important for the functions of brain regions receiving this dopamine innervation, and that imbalances in these dopamine release mechanisms may play a significant role in psychiatric disorders such as schizophrenia.

Gating of hippocampal-evoked activity in prefrontal cortical neurons by inputs from the mediodorsal thalamus and ventral tegmental area.

Projections from the hippocampus, the mediodorsal thalamus (MD), and the ventral tegmental area (VTA) form interconnected neural circuits that converge in the prefrontal cortex (PFC) to participate in the regulation of executive functions. The present study assessed the roles that the MD and VTA play in regulating the hippocampal-PFC pathway using extracellular single-unit recordings in urethane-anesthetized rats. MD stimulation inhibited PFC neuron firing (approximately 100 msec duration) evoked by fimbria/fornix (FF) stimulation in a majority of neurons tested. However, this effect was reduced if activation of thalamocortical inputs occurred almost simultaneously (10 msec) with stimulation of the FF. In a separate population of neurons, burst stimulation of the MD produced a short-term (approximately 100 msec) inhibition or facilitation of FF-evoked firing in 66 and 33% of PFC neurons, respectively. Moreover, tetanic stimulation of the MD caused a longer-lasting (approximately 5 min) potentiation of FF-evoked firing. Burst stimulation of the VTA inhibited FF-evoked firing in a frequency-dependent manner: firing evoked by higher-frequency trains of pulses to the FF was less inhibited than firing evoked by single-pulse stimulation. The inhibitory actions of VTA stimulation were augmented by D1 receptor antagonism and attenuated by D2 and D4 antagonists. Moreover, stimulation of the MD 10 msec before stimulation of the FF attenuated the VTA-mediated inhibition of evoked firing. Thus, both the MD and VTA exert a complex gating action over PFC neural activity, either facilitating or inhibiting firing in the hippocampal-PFC pathway depending on the frequency and relative timing of the arrival of afferent input.

Regulation of striatal dopamine neurotransmission by nitric oxide: effector pathways and signaling mechanisms.

An important role for the reactive gas nitric oxide (NO) in regulating striatal dopaminergic neurotransmission was identified shortly after initial observations indicated that this unorthodox neurotransmitter mediates many of the influences of glutamatergic neurotransmission in the cerebellum, cortex, and hippocampus. While the precise actions of NO on striatal presynaptic and postsynaptic elements remain to be fully characterized, the recent application of sophisticated anatomical, neurochemical, and electrophysiological approaches to the study of nitrergic signaling has revealed that NO exerts a powerful influence both on tonic extracellular dopamine (DA) levels and phasic DA neuron spike activity via the modulation of intrinsic striatal mechanisms and striatonigral feedback loops. Although the nature of the NO-mediated modulatory influence on DA neurotransmission was initially clouded by seemingly conflicting neurochemical observations, a growing body of literature and understanding of the diverse signaling mechanisms and effector pathways utilized by NO indicates that NO exerts a primary facilitatory influence over tonic and phasic dopaminergic neurotransmission under physiological conditions. A review of neurochemical and electrophysiological studies examining the influence of endogenous and exogenous NO on DA neurotransmission indicates that NO signaling exerts multiple effects on local striatal circuits and projection neurons involved in regulating basal ganglia output and nigrostriatal DA neuron activity. In addition to summarizing these influences, the current review focuses on the mechanisms utilized by striatal NO signaling pathways involved in modulating DA transmission at the level of the terminal and cell body and attempts to integrate these observations into a functional model of NO-dependent regulation of basal ganglia systems.