Biology subjects

Gunn, B. G.

Publications and source records attributed to Gunn, B. G..

4 recordsLinked to original sources

bioRxiv2023

Input / Output Relationships for the Primary Hippocampal Circuit.

The hippocampus is likely the most studied brain region but little is known about signal throughput -- the simplest, yet most essential of circuit operations -- across its multiple stages from perforant path input to CA1. Here we report that single pulse stimulation of the lateral perforant path (LPP) produces a two-part CA1 response generated by projections to CA3 ("direct path") and the dentate gyrus ("indirect path"). The latter was by far the more potent in driving CA1 output because it engaged the massive recurrent collateral system and elicited a series of fEPSPs and spikes in CA3. The mobilization time for this stereotyped sharp wave-like response resulted in surprisingly slow throughput. The circuit did not convey high frequency LPP trains but transmitted single pulses, or bursts of pulses separated by the period of the theta wave. During these activation patterns CA1 output faithfully reproduced a version of the LPP input. We conclude that the basic hippocampal circuit, despite its considerable complexity, has a default mode in which select cortical signals are reliably transferred to output stations. Significance statementThe hippocampus, a brain structure synonymous with episodic memory, is one of the most studied brain regions in neuroscience today. However, despite this intense interest, surprisingly little is known about how signals are transformed and processed by the hippocampal circuit. As a result, there are currently no "bottom up" hypotheses about how the structure supports its physiological function(s). Here, we use a novel brain slice preparation to describe the signal transformations occurring across the primary hippocampal circuit. The results identify novel circuit operations that challenge the notion of the tri-synaptic circuit and provide evidence for frequency-dependent filters that are critical for determining signal throughput. These findings provide an initial link between basic circuit function(s) and events recorded in behaving animals.

neuroscience↗

bioRxiv2022

Stress-induced plasticity of a novel CRH GABA projection disrupts reward behaviors

Disrupted operations of the reward circuit are thought to underlie major emotional disorders including depression and drug abuse1-3. These disorders commonly arise following early life stress4,5; however, how stress early in life enduringly impacts reward circuit functions to promote disease remains unclear. Here, we discover and characterize a novel stress-sensitive reward-circuit projection connecting the basolateral amygdala (BLA) and nucleus accumbens (NAc) that co-expresses GABA and the stress-reactive neuropeptide corticotropin-releasing hormone (CRH). We then identify a crucial role for this projection in executing the disrupted reward behaviors provoked by early-life adversity (ELA): Chemogenetic and optogenetic stimulations of the CRHGABA BLA[->]NAc projection in typically reared mice suppressed several reward seeking behaviors, recapitulating deficits resulting from ELA and demonstrating a key contribution of this pathway in the normal operations of the reward circuit. Next, inhibition of the CRHGABA BLA[->]NAc projection in adult mice that experienced ELA restored typical reward behaviors in these mice, and, in contrast, had little effect in typically reared mice, indicating a selective ELA-induced maladaptive plasticity of this reward-circuit projection. We discover a novel, stress-sensitive, reward inhibiting projection from the BLA[->]NAc with unique molecular features, which may provide targets for intervention in disabling mental illnesses.

neuroscience↗

bioRxiv2021

Impaired developmental microglial pruning of excitatory synapses on CRH-expressing hypothalamic neurons exacerbates stress responses throughout life

The developmental origins of stress-related mental illnesses are well-established, and early-life stress/adversity (ELA) is an important risk factor. However, it is unclear how ELA impacts the maturation of salient brain circuits, provoking enduring vulnerability to stress and stress-related disorders. Here we find that ELA increases the number and function of excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, and implicate disrupted synapse pruning by microglia as a key mechanism. Microglial process dynamics on live imaging, and engulfment of synaptic elements by microglia, were both attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor Mer. Accordingly, selective chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Selective early-life microglial activation also mitigated the adrenal hypertrophy and prolonged stress responses in adult ELA mice, establishing microglial actions during development as powerful contributors to experience-dependent sculpting of stress-related brain circuits.

neuroscience↗

bioRxiv2019

Acquisition of Temporal Order Involves a Reverberating Network in Hippocampal Field CA3

Here we report that hippocampal field CA3 maintains self-sustained activity for remarkable periods following a brief input and that this effect is extremely sensitive to minor perturbations. Using novel behavioral tests, that as with human episodic learning do not involve training or explicit rewards, we show that partial silencing of the network in mice blocks acquisition of temporal order, but not the identity or location, of odors. These results suggest a solution to the question of how hippocampus adds time to episodic memories.

neuroscience↗