Barn owls integrate spatial information across frequency channels to localize sounds in space. We... more Barn owls integrate spatial information across frequency channels to localize sounds in space. We presented barn owls with synchronous sounds that contained different bands of frequencies (3-5 kHz and 7-9 kHz) from different locations in space. When the owls were confronted with the conflicting localization cues from two synchronous sounds of equal level, their orienting responses were dominated by one of the sounds: they oriented toward the location of the low frequency sound when the sources were separated in azimuth; in contrast, they oriented toward the location of the high frequency sound when the sources were separated in elevation. We identified neural correlates of this behavioral effect in the optic tectum (OT, superior colliculus in mammals), which contains a map of auditory space and is involved in generating orienting movements to sounds. We found that low frequency cues dominate the representation of sound azimuth in the OT space map, whereas high frequency cues dominat...
To make appropriate choices, organisms must weigh the costs and benefits of potential valuable ou... more To make appropriate choices, organisms must weigh the costs and benefits of potential valuable outcomes, a process known to involve the nucleus accumbens (NAc) and its dopaminergic input. However, it is currently unknown if dopamine dynamically tracks alterations in expected reward value online as behavioral preferences change and if so, if it is causally linked to specific components of value such as reward magnitude and/or delay to reinforcement. Electrochemical methods were used to measure subsecond NAc dopamine release during a delay discounting task where magnitude was fixed but delay varied across blocks (n = 7 rats). Next, to assess whether this dopamine signaling was causally related to specific components of choice behavior, we employed selective optogenetic stimulation of dopamine terminals in the NAc using a modified delay discounting task in which both delay and magnitude varied independently (n = 23 rats). Cues predictive of available choices evoked dopamine release that scaled with the rat's preferred choices and dynamically shifted as delay to reinforcement for the large reward increased. In the second experiment, dopamine signaling was causally related to features of decision making, as optogenetically enhanced dopamine release within the NAc during predictive cue presentation was sufficient to alter subsequent value-related choices. Importantly, this dopamine-mediated shift in choice was limited to delay-based, but not magnitude-based, decisions. These findings indicate that NAc dopamine dynamically tracks delay discounting and establishes a causal role for this signaling in a subset of value-based associative strategies.
Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior to... more Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc) of urethane-anesthetized rats. We targeted halorhodopsin (NpHR) specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA) of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre + rats). Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.
Release of acetylcholine has been considered to originate exclusively from a subtype of striatal ... more Release of acetylcholine has been considered to originate exclusively from a subtype of striatal interneuron that provides widespread innervation of the striatum. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei indirectly influence the activity of the dorsal striatum and nucleus accumbens through their innervation of dopamine and thalamic neurons, which in turn converge at the same striatal levels. Here we show that cholinergic neurons in the brainstem also provide a direct innervation of the striatal complex. By the expression of fluorescent proteins in choline acetyltransferase (ChAT)::Cre ϩ transgenic rats, we selectively labeled cholinergic neurons in the rostral PPN, caudal PPN, and LDT. We show that cholinergic neurons topographically innervate wide areas of the striatal complex: rostral PPN preferentially innervates the dorsolateral striatum, and LDT preferentially innervates the medial striatum and nucleus accumbens core in which they principally form asymmetric synapses. Retrograde labeling combined with immunohistochemistry in wild-type rats confirmed the topography and cholinergic nature of the projection. Furthermore, transynaptic gene activation and conventional double retrograde labeling suggest that LDT neurons that innervate the nucleus accumbens also send collaterals to the thalamus and the dopaminergic midbrain, thus providing both direct and indirect projections, to the striatal complex. The differential activity of cholinergic interneurons and cholinergic neurons of the brainstem during reward-related paradigms suggest that the two systems play different but complementary roles in the processing of information in the striatum.
The C1 neurons are a nodal point for blood pressure control and other autonomic responses. Here w... more The C1 neurons are a nodal point for blood pressure control and other autonomic responses. Here we test whether these rostral ventrolateral medullary catecholaminergic (RVLM-CA) neurons use glutamate as a transmitter in the dorsal motor nucleus of the vagus (DMV). After injecting Cre-dependent adeno-associated virus (AAV2) DIO-Ef1α-channelrhodopsin2(ChR2)-mCherry (AAV2) into the RVLM of dopamine-β-hydroxylase Cre transgenic mice (DβH(Cre/0)), mCherry was detected exclusively in RVLM-CA neurons. Within the DMV >95% mCherry-immunoreactive(ir) axonal varicosities were tyrosine hydroxylase (TH)-ir and the same proportion were vesicular glutamate transporter 2 (VGLUT2)-ir. VGLUT2-mCherry colocalization was virtually absent when AAV2 was injected into the RVLM of DβH(Cre/0);VGLUT2(flox/flox) mice, into the caudal VLM (A1 noradrenergic neuron-rich region) of DβH(Cre/0) mice or into the raphe of ePet(Cre/0) mice. Following injection of AAV2 into RVLM of TH-Cre rats, phenylethanolamine N-methyl transferase and VGLUT2 immunoreactivities were highly colocalized in DMV within EYFP-positive or EYFP-negative axonal varicosities. Ultrastructurally, mCherry terminals from RVLM-CA neurons in DβH(Cre/0) mice made predominantly asymmetric synapses with choline acetyl-transferase-ir DMV neurons. Photostimulation of ChR2-positive axons in DβH(Cre/0) mouse brain slices produced EPSCs in 71% of tested DMV preganglionic neurons (PGNs) but no IPSCs. Photostimulation (20 Hz) activated PGNs up to 8 spikes/s (current-clamp). EPSCs were eliminated by tetrodotoxin, reinstated by 4-aminopyridine, and blocked by ionotropic glutamate receptor blockers. In conclusion, VGLUT2 is expressed by RVLM-CA (C1) neurons in rats and mice regardless of the presence of AAV2, the C1 neurons activate DMV parasympathetic PGNs monosynaptically and this connection uses glutamate as an ionotropic transmitter.
The neural basis of positive reinforcement is often studied in the laboratory using intracranial ... more The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS), a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA) dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc), a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.
Vision may dominate our perception of space not because of any inherent physiological advantage o... more Vision may dominate our perception of space not because of any inherent physiological advantage of visual over other sensory connections in the brain, but because visual information tends to be more reliable than other sources of spatial information, and the central nervous system integrates information in a statistically optimal fashion. This review discusses recent experiments on audiovisual integration that support this hypothesis. We consider candidate neural codes that would enable optimal integration and the implications of optimal integration for perception and plasticity.
Currently there is no general approach for achieving specific optogenetic control of geneticallyd... more Currently there is no general approach for achieving specific optogenetic control of geneticallydefined cell types in rats, which provide a powerful experimental system for numerous established neurophysiological and behavioral paradigms. To overcome this challenge we have generated genetically-restricted recombinase-driver rat lines suitable for driving gene expression in specific cell-types, expressing Cre recombinase under control of large genomic regulatory regions (200-300 Kb). Multiple tyrosine hydroxylase (Th)::Cre and choline acetyltransferase (Chat)::Cre lines were produced that exhibited specific opsin expression in targeted cell-types. We additionally developed methods for utilizing optogenetic tools in freely-moving rats, and leveraged these technologies to clarify the causal relationship between dopamine (DA) neuron firing and positive reinforcement, observing that optical stimulation of DA neurons in the ventral tegmental area (VTA) of Th::Cre rats is sufficient to support vigorous intracranial self-stimulation (ICSS). studies complement existing targeting approaches by extending generalizability of optogenetics to traditionally non-genetically-tractable but vital animal models.
The optic tectum of the barn owl contains a map of auditory space. We found that, in response to ... more The optic tectum of the barn owl contains a map of auditory space. We found that, in response to moving sounds, the locations of receptive fields that make up the map shifted toward the approaching sound. The magnitude of the receptive field shifts increased systematically with increasing stimulus velocity and, therefore, was appropriate to compensate for sensory and motor delays inherent to auditory orienting behavior. Thus, the auditory space map is not static, but shifts adaptively and dynamically in response to stimulus motion. We provide a computational model to account for these results. Because the model derives predictive responses from processes that are known to occur commonly in neural networks, we hypothesize that analogous predictive responses will be found to exist widely in the central nervous system. This hypothesis is consistent with perceptions of stimulus motion in humans for many sensory parameters.
Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new... more Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new learning. Often, this learning includes identifying cues that predict reward availability. Unexpected rewards strongly activate midbrain dopamine neurons. This phasic signal is proposed to support learning about antecedent cues by signaling discrepancies between actual and expected outcomes, termed a reward prediction error. However, it is unknown whether dopamine neuron prediction error signaling and cue-reward learning are causally linked. To test this hypothesis, we manipulated dopamine neuron activity in rats in two behavioral procedures, associative blocking and extinction, that illustrate the essential function of prediction errors in learning. We observed that optogenetic activation of dopamine neurons concurrent with reward delivery, mimicking a prediction error, was sufficient to cause long-lasting increases in cue-elicited reward-seeking behavior. Our findings establish a causal role for temporally precise dopamine neuron signaling in cue-reward learning, bridging a critical gap between experimental evidence and influential theoretical frameworks. npg
Major depression is characterized by diverse debilitating symptoms that include hopelessness and ... more Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia 1 . Dopamine neurons involved in reward and motivation 2-9 are among many neural populations that have been hypothesized to be relevant 10 , and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.
In the brain, mutual spatial alignment across different sensory representations can be shaped and... more In the brain, mutual spatial alignment across different sensory representations can be shaped and maintained through plasticity. Here, we use a Hebbian model to account for the synaptic plasticity that results from a displacement of the space representation for one input channel relative to that of another, when the synapses from both channels are equally plastic. Surprisingly, although the synaptic weights for the two channels obeyed the same Hebbian learning rule, the amount of plasticity exhibited by the respective channels was highly asymmetric and depended on the relative strength and width of the receptive fields (RFs): the channel with the weaker or broader RFs always exhibited most or all of the plasticity. A fundamental difference between our Hebbian model and most previous models is that in our model synaptic weights were normalized separately for each input channel, ensuring that the circuit would respond to both sensory inputs. The model produced three distinct regimes of plasticity dynamics (winner-take-all, mixed-shift, and no-shift), with the transition between the regimes depending on the size of the spatial displacement and the degree of correlation between the sensory channels. In agreement with experimental observations, plasticity was enhanced by the accumulation of incremental adaptive adjustments to a sequence of small displacements. These same principles would apply not only to the maintenance of spatial registry across input channels, but also to the experience-dependent emergence of aligned representations in developing circuits.
1 6 3 t e C h n I C a l r e p O r t S Recent advances in optogenetics have improved the precision... more 1 6 3 t e C h n I C a l r e p O r t S Recent advances in optogenetics have improved the precision with which defined circuit elements can be controlled optically in freely moving mammals; in particular, recombinase-dependent opsin viruses, used with a growing pool of transgenic mice expressing recombinases, allow manipulation of specific cell types. However, although optogenetic control has allowed neural circuits to be manipulated in increasingly powerful ways, combining optogenetic stimulation with simultaneous multichannel electrophysiological readout of isolated units in freely moving mice remains a challenge. We designed and validated the optetrode, a device that allows for colocalized multi-tetrode electrophysiological recording and optical stimulation in freely moving mice. Optetrode manufacture employs a unique optical fiber-centric coaxial design approach that yields a lightweight (2 g), compact and robust device that is suitable for behaving mice. This low-cost device is easy to construct (2.5 h to build without specialized equipment). We found that the drive design produced stable high-quality recordings and continued to do so for at least 6 weeks following implantation. We validated the optetrode by quantifying, for the first time, the response of cells in the medial prefrontal cortex to local optical excitation and inhibition, probing multiple different genetically defined classes of cells in the mouse during open field exploration.
Barn owls integrate spatial information across frequency channels to localize sounds in space. We... more Barn owls integrate spatial information across frequency channels to localize sounds in space. We presented barn owls with synchronous sounds that contained different bands of frequencies (3-5 kHz and 7-9 kHz) from different locations in space. When the owls were confronted with the conflicting localization cues from two synchronous sounds of equal level, their orienting responses were dominated by one of the sounds: they oriented toward the location of the low frequency sound when the sources were separated in azimuth; in contrast, they oriented toward the location of the high frequency sound when the sources were separated in elevation. We identified neural correlates of this behavioral effect in the optic tectum (OT, superior colliculus in mammals), which contains a map of auditory space and is involved in generating orienting movements to sounds. We found that low frequency cues dominate the representation of sound azimuth in the OT space map, whereas high frequency cues dominat...
To make appropriate choices, organisms must weigh the costs and benefits of potential valuable ou... more To make appropriate choices, organisms must weigh the costs and benefits of potential valuable outcomes, a process known to involve the nucleus accumbens (NAc) and its dopaminergic input. However, it is currently unknown if dopamine dynamically tracks alterations in expected reward value online as behavioral preferences change and if so, if it is causally linked to specific components of value such as reward magnitude and/or delay to reinforcement. Electrochemical methods were used to measure subsecond NAc dopamine release during a delay discounting task where magnitude was fixed but delay varied across blocks (n = 7 rats). Next, to assess whether this dopamine signaling was causally related to specific components of choice behavior, we employed selective optogenetic stimulation of dopamine terminals in the NAc using a modified delay discounting task in which both delay and magnitude varied independently (n = 23 rats). Cues predictive of available choices evoked dopamine release that scaled with the rat's preferred choices and dynamically shifted as delay to reinforcement for the large reward increased. In the second experiment, dopamine signaling was causally related to features of decision making, as optogenetically enhanced dopamine release within the NAc during predictive cue presentation was sufficient to alter subsequent value-related choices. Importantly, this dopamine-mediated shift in choice was limited to delay-based, but not magnitude-based, decisions. These findings indicate that NAc dopamine dynamically tracks delay discounting and establishes a causal role for this signaling in a subset of value-based associative strategies.
Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior to... more Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc) of urethane-anesthetized rats. We targeted halorhodopsin (NpHR) specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA) of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre + rats). Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.
Release of acetylcholine has been considered to originate exclusively from a subtype of striatal ... more Release of acetylcholine has been considered to originate exclusively from a subtype of striatal interneuron that provides widespread innervation of the striatum. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei indirectly influence the activity of the dorsal striatum and nucleus accumbens through their innervation of dopamine and thalamic neurons, which in turn converge at the same striatal levels. Here we show that cholinergic neurons in the brainstem also provide a direct innervation of the striatal complex. By the expression of fluorescent proteins in choline acetyltransferase (ChAT)::Cre ϩ transgenic rats, we selectively labeled cholinergic neurons in the rostral PPN, caudal PPN, and LDT. We show that cholinergic neurons topographically innervate wide areas of the striatal complex: rostral PPN preferentially innervates the dorsolateral striatum, and LDT preferentially innervates the medial striatum and nucleus accumbens core in which they principally form asymmetric synapses. Retrograde labeling combined with immunohistochemistry in wild-type rats confirmed the topography and cholinergic nature of the projection. Furthermore, transynaptic gene activation and conventional double retrograde labeling suggest that LDT neurons that innervate the nucleus accumbens also send collaterals to the thalamus and the dopaminergic midbrain, thus providing both direct and indirect projections, to the striatal complex. The differential activity of cholinergic interneurons and cholinergic neurons of the brainstem during reward-related paradigms suggest that the two systems play different but complementary roles in the processing of information in the striatum.
The C1 neurons are a nodal point for blood pressure control and other autonomic responses. Here w... more The C1 neurons are a nodal point for blood pressure control and other autonomic responses. Here we test whether these rostral ventrolateral medullary catecholaminergic (RVLM-CA) neurons use glutamate as a transmitter in the dorsal motor nucleus of the vagus (DMV). After injecting Cre-dependent adeno-associated virus (AAV2) DIO-Ef1α-channelrhodopsin2(ChR2)-mCherry (AAV2) into the RVLM of dopamine-β-hydroxylase Cre transgenic mice (DβH(Cre/0)), mCherry was detected exclusively in RVLM-CA neurons. Within the DMV >95% mCherry-immunoreactive(ir) axonal varicosities were tyrosine hydroxylase (TH)-ir and the same proportion were vesicular glutamate transporter 2 (VGLUT2)-ir. VGLUT2-mCherry colocalization was virtually absent when AAV2 was injected into the RVLM of DβH(Cre/0);VGLUT2(flox/flox) mice, into the caudal VLM (A1 noradrenergic neuron-rich region) of DβH(Cre/0) mice or into the raphe of ePet(Cre/0) mice. Following injection of AAV2 into RVLM of TH-Cre rats, phenylethanolamine N-methyl transferase and VGLUT2 immunoreactivities were highly colocalized in DMV within EYFP-positive or EYFP-negative axonal varicosities. Ultrastructurally, mCherry terminals from RVLM-CA neurons in DβH(Cre/0) mice made predominantly asymmetric synapses with choline acetyl-transferase-ir DMV neurons. Photostimulation of ChR2-positive axons in DβH(Cre/0) mouse brain slices produced EPSCs in 71% of tested DMV preganglionic neurons (PGNs) but no IPSCs. Photostimulation (20 Hz) activated PGNs up to 8 spikes/s (current-clamp). EPSCs were eliminated by tetrodotoxin, reinstated by 4-aminopyridine, and blocked by ionotropic glutamate receptor blockers. In conclusion, VGLUT2 is expressed by RVLM-CA (C1) neurons in rats and mice regardless of the presence of AAV2, the C1 neurons activate DMV parasympathetic PGNs monosynaptically and this connection uses glutamate as an ionotropic transmitter.
The neural basis of positive reinforcement is often studied in the laboratory using intracranial ... more The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS), a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA) dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc), a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.
Vision may dominate our perception of space not because of any inherent physiological advantage o... more Vision may dominate our perception of space not because of any inherent physiological advantage of visual over other sensory connections in the brain, but because visual information tends to be more reliable than other sources of spatial information, and the central nervous system integrates information in a statistically optimal fashion. This review discusses recent experiments on audiovisual integration that support this hypothesis. We consider candidate neural codes that would enable optimal integration and the implications of optimal integration for perception and plasticity.
Currently there is no general approach for achieving specific optogenetic control of geneticallyd... more Currently there is no general approach for achieving specific optogenetic control of geneticallydefined cell types in rats, which provide a powerful experimental system for numerous established neurophysiological and behavioral paradigms. To overcome this challenge we have generated genetically-restricted recombinase-driver rat lines suitable for driving gene expression in specific cell-types, expressing Cre recombinase under control of large genomic regulatory regions (200-300 Kb). Multiple tyrosine hydroxylase (Th)::Cre and choline acetyltransferase (Chat)::Cre lines were produced that exhibited specific opsin expression in targeted cell-types. We additionally developed methods for utilizing optogenetic tools in freely-moving rats, and leveraged these technologies to clarify the causal relationship between dopamine (DA) neuron firing and positive reinforcement, observing that optical stimulation of DA neurons in the ventral tegmental area (VTA) of Th::Cre rats is sufficient to support vigorous intracranial self-stimulation (ICSS). studies complement existing targeting approaches by extending generalizability of optogenetics to traditionally non-genetically-tractable but vital animal models.
The optic tectum of the barn owl contains a map of auditory space. We found that, in response to ... more The optic tectum of the barn owl contains a map of auditory space. We found that, in response to moving sounds, the locations of receptive fields that make up the map shifted toward the approaching sound. The magnitude of the receptive field shifts increased systematically with increasing stimulus velocity and, therefore, was appropriate to compensate for sensory and motor delays inherent to auditory orienting behavior. Thus, the auditory space map is not static, but shifts adaptively and dynamically in response to stimulus motion. We provide a computational model to account for these results. Because the model derives predictive responses from processes that are known to occur commonly in neural networks, we hypothesize that analogous predictive responses will be found to exist widely in the central nervous system. This hypothesis is consistent with perceptions of stimulus motion in humans for many sensory parameters.
Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new... more Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new learning. Often, this learning includes identifying cues that predict reward availability. Unexpected rewards strongly activate midbrain dopamine neurons. This phasic signal is proposed to support learning about antecedent cues by signaling discrepancies between actual and expected outcomes, termed a reward prediction error. However, it is unknown whether dopamine neuron prediction error signaling and cue-reward learning are causally linked. To test this hypothesis, we manipulated dopamine neuron activity in rats in two behavioral procedures, associative blocking and extinction, that illustrate the essential function of prediction errors in learning. We observed that optogenetic activation of dopamine neurons concurrent with reward delivery, mimicking a prediction error, was sufficient to cause long-lasting increases in cue-elicited reward-seeking behavior. Our findings establish a causal role for temporally precise dopamine neuron signaling in cue-reward learning, bridging a critical gap between experimental evidence and influential theoretical frameworks. npg
Major depression is characterized by diverse debilitating symptoms that include hopelessness and ... more Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia 1 . Dopamine neurons involved in reward and motivation 2-9 are among many neural populations that have been hypothesized to be relevant 10 , and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.
In the brain, mutual spatial alignment across different sensory representations can be shaped and... more In the brain, mutual spatial alignment across different sensory representations can be shaped and maintained through plasticity. Here, we use a Hebbian model to account for the synaptic plasticity that results from a displacement of the space representation for one input channel relative to that of another, when the synapses from both channels are equally plastic. Surprisingly, although the synaptic weights for the two channels obeyed the same Hebbian learning rule, the amount of plasticity exhibited by the respective channels was highly asymmetric and depended on the relative strength and width of the receptive fields (RFs): the channel with the weaker or broader RFs always exhibited most or all of the plasticity. A fundamental difference between our Hebbian model and most previous models is that in our model synaptic weights were normalized separately for each input channel, ensuring that the circuit would respond to both sensory inputs. The model produced three distinct regimes of plasticity dynamics (winner-take-all, mixed-shift, and no-shift), with the transition between the regimes depending on the size of the spatial displacement and the degree of correlation between the sensory channels. In agreement with experimental observations, plasticity was enhanced by the accumulation of incremental adaptive adjustments to a sequence of small displacements. These same principles would apply not only to the maintenance of spatial registry across input channels, but also to the experience-dependent emergence of aligned representations in developing circuits.
1 6 3 t e C h n I C a l r e p O r t S Recent advances in optogenetics have improved the precision... more 1 6 3 t e C h n I C a l r e p O r t S Recent advances in optogenetics have improved the precision with which defined circuit elements can be controlled optically in freely moving mammals; in particular, recombinase-dependent opsin viruses, used with a growing pool of transgenic mice expressing recombinases, allow manipulation of specific cell types. However, although optogenetic control has allowed neural circuits to be manipulated in increasingly powerful ways, combining optogenetic stimulation with simultaneous multichannel electrophysiological readout of isolated units in freely moving mice remains a challenge. We designed and validated the optetrode, a device that allows for colocalized multi-tetrode electrophysiological recording and optical stimulation in freely moving mice. Optetrode manufacture employs a unique optical fiber-centric coaxial design approach that yields a lightweight (2 g), compact and robust device that is suitable for behaving mice. This low-cost device is easy to construct (2.5 h to build without specialized equipment). We found that the drive design produced stable high-quality recordings and continued to do so for at least 6 weeks following implantation. We validated the optetrode by quantifying, for the first time, the response of cells in the medial prefrontal cortex to local optical excitation and inhibition, probing multiple different genetically defined classes of cells in the mouse during open field exploration.
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Papers by Ilana Witten