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• Anion transport by aluminium-activated malate transporter (ALMT) proteins is negatively regulated by gamma-aminobutyric acid (GABA), which increases in concentration during stress. • Here, the interaction between GABA and wheat (Triticum aestivum, Ta) TaALMT1 heterologously-expressed in Xenopus laevis oocytes was investigated. • GABA inhibited anion transport by TaALMT1 in membrane patches from the cytosolic, not extracellular membrane face, via a reduction in open probability (NPopen), not an inhibition of channel current magnitude. TaALMT1 currents in patches frequently exhibited rundown with complete removal of cytosolic factors, but were partially sustained by protein kinase C dependent phosphorylation. When applied to whole oocytes a GABA-analogue-BODIPY conjugate inhibited TaALMT1 anion currents from the cytoplasmic face only, whereas free GABA inhibited from both the inside and outside consistent with GABA traversing the TaALMT1 pore then acting from the inside. • We propose GABA does not competitively inhibit ALMT conductance through the same pore but rather leads to an allosteric effect, reducing anion channel opening frequency. Across plants GABA is a conserved regulator of anion transport via ALMTs – a family with numerous physiological roles beyond Al3+ tolerance. Our data suggests that a GABA–ALMT interaction from the cytosolic face has the potential to form part of a novel plant signalling pathway.

Chronic pain easily leads to concomitant mood disorders, and the excitability of anterior cingulate cortex (ACC) pyramidal neurons (PNs) is involved in chronic pain-related anxiety. However, the mechanism by which PNs regulate pain-related anxiety is still unknown. The GABAergic system plays an important role in modulating neuronal activity. In this paper, we aimed to study how the GABAergic system participates in regulating the excitability of ACC PNs, consequently affecting chronic inflammatory pain-related anxiety. A rat model of CFA-induced chronic inflammatory pain displayed anxiety-like behaviors, increased the excitability of ACC PNs, and reduced inhibitory presynaptic transmission; however, the number of GAD65/67 was not altered. Interestingly, intra-ACC injection of the GABA A R agonist muscimol relieved anxiety-like behaviors but had no effect on chronic inflammatory pain. Intra-ACC injection of the GABA A R antagonist picrotoxin induced anxiety-like behaviors but had no effect on pain in normal rats. Notably, chemogenetic activation of GABAergic neurons in the ACC alleviated chronic inflammatory pain and pain-induced anxiety-like behaviors, enhanced inhibitory presynaptic transmission, and reduced the excitability of ACC PNs. Chemogenetic inhibition of GABAergic neurons in the ACC led to pain-induced anxiety-like behaviors, reduced inhibitory presynaptic transmission, and enhanced the excitability of ACC PNs but had no effect on pain in normal rats. We demonstrate that the GABAergic system mediates a reduction in inhibitory presynaptic transmission in the ACC, which leads to enhanced excitability of pyramidal neurons in the ACC and is associated with chronic inflammatory pain-related anxiety.

Motivation facilitates recovery after neuronal damage, but its mechanism is elusive. It is generally thought that the nucleus accumbens (NAc) regulates motivation-driven effort but is not involved in the direct control of movement. Using causality analysis, we identified the flow of activity from the NAc to the sensorimotor cortex (SMC) during the recovery of dexterous finger movements after spinal cord injury at the cervical level in macaque monkeys. Furthermore, reversible pharmacological inactivation of the NAc during the early recovery period diminished high-frequency oscillatory activity in the SMC, which was accompanied by a transient deficit of amelioration in finger dexterity obtained by rehabilitation. These results demonstrate that during recovery after spinal damage, the NAc up-regulates the high-frequency activity of the SMC and is directly involved in the control of finger movements.

Although the hippocampus has long been linked to planning, it has not been shown to be necessary for planning behavior. Using computational modeling and a new rat task that allows the quantification of planning behavior across many repeated trials, the authors report the first evidence that hippocampal inactivation impairs planning. Planning can be defined as action selection that leverages an internal model of the outcomes likely to follow each possible action. Its neural mechanisms remain poorly understood. Here we adapt recent advances from human research for rats, presenting for the first time an animal task that produces many trials of planned behavior per session, making multitrial rodent experimental tools available to study planning. We use part of this toolkit to address a perennially controversial issue in planning: the role of the dorsal hippocampus. Although prospective hippocampal representations have been proposed to support planning, intact planning in animals with damaged hippocampi has been repeatedly observed. Combining formal algorithmic behavioral analysis with muscimol inactivation, we provide causal evidence directly linking dorsal hippocampus with planning behavior. Our results and methods open the door to new and more detailed investigations of the neural mechanisms of planning in the hippocampus and throughout the brain.

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABA A R) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO’s synthetic enzyme ( akr1c14 ) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABA A R agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders. Placental dysfunction has been implicated in abnormal neurodevelopment. Vacher et al. found that loss of a neuroactive hormone from the placenta alters brain development in a regional and sex-linked manner, resulting in autism-like behaviors in male offspring.

The average surface pH of the ocean is dropping at a rapid rate due to the dissolution of anthropogenic CO2, raising concerns for marine life. Additionally, some coastal areas periodically experience upwelling of CO2-enriched water with reduced pH. Previous research has demonstrated ocean acidification (OA)-induced changes in behavioural and sensory systems including olfaction, which is due to altered function of neural gamma-aminobutyric acid type A (GABAA) receptors. Here, we used a camera-based tracking software system to examine whether OA-dependent changes in GABAA receptors affect anxiety in juvenile Californian rockfish (Sebastes diploproa). Anxiety was estimated using behavioural tests that measure light/dark preference (scototaxis) and proximity to an object. After one week in OA conditions projected for the next century in the California shore (1125 ± 100 µatm, pH 7.75), anxiety was significantly increased relative to controls (483 ± 40 µatm CO2, pH 8.1). The GABAA-receptor agonist muscimol, but not the antagonist gabazine, caused a significant increase in anxiety consistent with altered Cl− flux in OA-exposed fish. OA-exposed fish remained more anxious even after 7 days back in control seawater; however, they resumed their normal behaviour by day 12. These results show that OA could severely alter rockfish behaviour; however, this effect is reversible.

In patients with damage to the primary visual cortex (V1), residual vision can guide goal-directed movements to targets in the blind field without awareness. This phenomenon has been termed blindsight, and its neural mechanisms are controversial. There should be visual pathways to the higher visual cortices bypassing V1, however some literature propose that the signal is mediated by the superior colliculus (SC) and pulvinar, while others claim the dorsal lateral geniculate nucleus (dLGN) transmits the signal. Here, we directly test the role of SC to ventrolateral pulvinar (vlPul) pathway in blindsight monkeys. Pharmacological inactivation of vlPul impairs visually guided saccades (VGS) in the blind field. Selective and reversible blockade of the SC-vlPul pathway by combining two viral vectors also impairs VGS. With these results we claim the SC-vlPul pathway contributes to blindsight. The discrepancy would be due to the extent of retrograde degeneration of dLGN and task used for assessment. Blindsight refers to visual behaviours that are spared following lesions to the primary visual cortex and is thought to involve pulvinar circuits. Here, the authors report that selective inactivation of the ventral pulvinar or the superior colliculus leads to impairment in visually guided saccades in blindsight.

Wang and colleagues find that weakening hippocampal theta in a familiar environment reduces the performance of rats in a spatial memory task, decreases the number of theta sequences and degrades internally generated hippocampal episode cell firing, while leaving place cell firing intact. The same weakening of theta also prevents the formation of a precise spatial representation in a novel environment unless proximal cues are present. Together these results suggest that the mechanisms underlying internally generated hippocampal sequences of activity are crucial for episodic memory. Sensory cue inputs and memory-related internal brain activities govern the firing of hippocampal neurons, but which specific firing patterns are induced by either of the two processes remains unclear. We found that sensory cues guided the firing of neurons in rats on a timescale of seconds and supported the formation of spatial firing fields. Independently of the sensory inputs, the memory-related network activity coordinated the firing of neurons not only on a second-long timescale, but also on a millisecond-long timescale, and was dependent on medial septum inputs. We propose a network mechanism that might coordinate this internally generated firing. Overall, we suggest that two independent mechanisms support the formation of spatial firing fields in hippocampus, but only the internally organized system supports short-timescale sequential firing and episodic memory.

Targeted manipulations of neural activity are essential approaches in neuroscience and neurology, but monitoring such procedures in the living brain remains a significant challenge. Here we introduce a paramagnetic analog of the drug muscimol that enables targeted neural inactivation to be performed with feedback from magnetic resonance imaging. We validate pharmacological properties of the compound in vitro, and show that its distribution in vivo reliably predicts perturbations to brain activity. Targeted manipulations of neural activity in the living brain remain a significant challenge. In this study the authors introduce a paramagnetic analog of the drug muscimol that enables targeted neural inactivation to be performed with feedback from magnetic resonance imaging

The rostromedial caudate (rmCD) of primates is thought to contribute to reward value processing, but a causal relationship has not been established. Here we use an inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drug) to repeatedly and non-invasively inactivate rmCD of macaque monkeys. We inject an adeno-associated viral vector expressing the inhibitory DREADD, hM4Di, into the rmCD bilaterally. To visualize DREADD expression in vivo , we develop a non-invasive imaging method using positron emission tomography (PET). PET imaging provides information critical for successful chemogenetic silencing during experiments, in this case the location and level of hM4Di expression, and the relationship between agonist dose and hM4Di receptor occupancy. Here we demonstrate that inactivating bilateral rmCD through activation of hM4Di produces a significant and reproducible loss of sensitivity to reward value in monkeys. Thus, the rmCD is involved in making normal judgments about the value of reward. Processing the value of reward is thought to involve the rostromedial caudate (rmCD), but a causal demonstration is lacking in primates. Here the authors use chemogenetics and PET imaging to show that inactivation of rmCD leads to impairments in reward value judgments.