SUMMARY Although hippocampal CA1 pyramidal neurons (PNs) were thought to comprise a uniform population, recent evidence supports two distinct sublayers along the radial axis, with deep neurons more likely to form place cells than superficial neurons. CA1 PNs also differ along the transverse axis with regard to direct inputs from entorhinal cortex (EC), with medial EC (MEC) providing spatial information to PNs toward CA2 (proximal CA1) and lateral EC (LEC) providing non-spatial information to PNs toward subiculum (distal CA1). We demonstrate that the two inputs differentially activate the radial sublayers and that this difference reverses along the transverse axis, with MEC preferentially targeting deep PNs in proximal CA1 and LEC preferentially exciting superficial PNs in distal CA1. This differential excitation reflects differences in dendritic spine numbers. Our results reveal a heterogeneity in EC-CA1 connectivity that may help explain differential roles of CA1 PNs in spatial and non-spatial learning and memory.

Summary Flexibly adapting to novel situations is critical for survival, which is impaired in neuropsychiatric disorders 1 . Thus, understanding whether and how novelty prepares, or primes, brain circuitry to facilitate cognitive flexibility has important translational relevance. Novelty recruits the hippocampus and medial prefrontal cortex (mPFC) 2 and may prime hippocampal-prefrontal circuitry for subsequent learning-associated plasticity. We find that novelty resets ventral hippocampal-prefrontal (vHPC-mPFC) circuitry and facilitates overcoming an established strategy. Exposing mice to novelty disrupted a previously encoded strategy by reorganizing vHPC activity to local theta (4–12 Hz) oscillations and weakening existing vHPC-mPFC connectivity. As mice subsequently adapted to a new task, vHPC neurons developed new task-associated activity, vHPC-mPFC connectivity was strengthened, and mPFC neurons updated encoding with new rules. Without novelty, mice adhered to their established strategy. Blocking dopamine D1-receptors (D1Rs) or inhibiting novelty-tagged cells expressing D1Rs in the vHPC prevented these behavioral and physiological effects of novelty. Further, D1R activation mimicked the effects of novelty. These results suggest that novelty promotes adaptive learning by D1R-mediated resetting of vHPC-mPFC circuitry, thereby enabling learning-associated circuit plasticity.

Alcohol has many effects on brain function and hence on human behavior, ranging from anxiolytic and mild disinhibitory effects, sedation and motor incoordination, amnesia, emesis, hypnosis and eventually unconsciousness. In recent years a variety of studies have shown that acute and chronic exposure to alcohol can modulate ion channels that regulate excitability. Modulation of intrinsic excitability provides another way in which alcohol can influence neuronal network activity, in addition to its actions on synaptic inputs. In this review, we review “low dose” effects [between 2–20mM EtOH], and medium dose effects [between 20–50mM, by considering in turn each of the many networks and brain regions affected by alcohol, and thereby attempt to integrate in vitro physiological studies in specific brain regions (e.g. amygdala, ventral tegmental area, prefrontal cortex, thalamus, cerebellum etc..) within the context of alcohol’s behavioral actions in vivo (e.g. anxiolysis, euphoria, sedation, motor incoordination).

Neuronal inhibition can occur via synaptic mechanisms or through tonic activation of extrasynaptic receptors. In spinal cord, glycine mediates synaptic inhibition through the activation of heteromeric glycine receptors (GlyRs) composed primarily of α1 and β subunits. Inhibitory GlyRs are also found throughout the brain, where GlyR α2 and α3 subunit expression exceeds that of α1, particularly in forebrain structures, and coassembly of these α subunits with the β subunit appears to occur to a lesser extent than in spinal cord. Here, we analyzed GlyR currents in several regions of the adolescent mouse forebrain (striatum, prefrontal cortex, hippocampus, amygdala, and bed nucleus of the stria terminalis). Our results show ubiquitous expression of GlyRs that mediate large-amplitude currents in response to exogenously applied glycine in these forebrain structures. Additionally, tonic inward currents were also detected, but only in the striatum, hippocampus, and prefrontal cortex (PFC). These tonic currents were sensitive to both strychnine and picrotoxin, indicating that they are mediated by extrasynaptic homomeric GlyRs. Recordings from mice deficient in the GlyR α3 subunit (Glra3 −/− ) revealed a lack of tonic GlyR currents in the striatum and the PFC. In Glra2 −/Y animals, GlyR tonic currents were preserved; however, the amplitudes of current responses to exogenous glycine were significantly reduced. We conclude that functional α2 and α3 GlyRs are present in various regions of the forebrain and that α3 GlyRs specifically participate in tonic inhibition in the striatum and PFC. Our findings suggest roles for glycine in regulating neuronal excitability in the forebrain.glycine receptor | tonic inhibition | Cys-loop receptor | strychnine | alpha subunits

Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.